Begin with the Executive Dashboard (p. 3) for the 5-finding summary. Pages 02–04 are clinical-grade information; share with your physician. Pages 05–08 are the S21 mechanistic layers — these show how variant load propagates through your biology. Pages 09–12 are personal and lifestyle-oriented. Pages 13–16 consolidate findings into action. Appendices contain methodology, sample QC, and glossary — reach for them when interpreting any specific finding.
Cumulative risk projections by age for the top four conditions identified in this report. Solid lines = this genome (PRS + monogenic + lifestyle baseline); dashed lines = European female population average.
Estimates assume current Western lifestyle baseline; substantial modulation by diet, exercise, screening compliance, and pharmaceutical intervention is possible. Breast cancer trajectory reflects lifetime risk for BRCA1 pathogenic variant carriers (~55–65% by age 70 per published meta-analyses) integrated with the PRS contribution. CAD trajectory uses Khera et al. (2018) hazard-ratio-by-age estimates for the 95th PRS percentile.
Ranked by clinical actionability × confidence × mechanistic support.
Six-axis structural assessment. Solid = this genome; dashed = European reference cohort median.
Dominant: Structural (1.5× pop. median). Metabolic axis slightly elevated.
19/39 AIMs successfully genotyped; archaic panel: 6 markers.
4-marker archaic panel provides indicative signal only; full whole-genome Sankararaman inference would be more precise.
Variants meeting ACMG/AMP 2015 criteria for Pathogenic, Likely Pathogenic, or Uncertain Significance with informative evidence. Constraint badges integrate gnomAD (pLI), ClinGen dosage (HI/TS), and ClinGen Gene-Disease Validity (GDV).
| Variant | Gene | Effect | Constraint | Classification | ACMG evidence |
|---|---|---|---|---|---|
| 17:43094464 dupC |
BRCA1 | p.Gln1756Profs*74 frameshift, exon 19 |
pLI 1.00 HI: sufficient GDV: Definitive | Likely Pathogenic |
PVS1
PM2
PP3
PP5
|
| 17:7674220 G>A |
TP53 | p.Arg175His missense, DNA-binding domain |
pLI 1.00 HI: sufficient GDV: Definitive | VUS-favor-P |
PM1
PM2
PM5
PP3
AlphaMissense 0.98; in mutational hotspot
|
| 11:5226778 A>C |
HBB | p.Glu7Val (HbS) het carrier |
pLI 0.34 AR phenotype GDV: Definitive | Pathogenic (carrier) |
PS3
PS4
PP5
Het — carrier only, not affected
|
| 7:117559592 delCTT |
CFTR | ΔF508 het carrier |
pLI 0.10 AR phenotype GDV: Definitive | Pathogenic (carrier) |
PVS1
PS3
PS4
PP5
|
| 22:43089849 G>A |
CYP21A2 | p.Val281Leu het carrier |
pLI 0.05 AR phenotype GDV: Strong | Pathogenic (carrier) |
PS3
PM1
PP5
|
| 16:223675 G>A |
HBA1 | 3.7-kb deletion α-thal trait carrier |
pLI 0.02 AR phenotype GDV: Definitive | Pathogenic (carrier) |
PVS1
PS4
PP5
|
Heterozygous pathogenic variants in 122 autosomal-recessive disease genes. For each, partner screening recommended pre-conception. Reproductive risk assumes random-mating partner with population-baseline carrier frequency.
| Condition | Couple risk | If partner + |
|---|---|---|
| Cystic fibrosis (CFTR) | 1 in 100 | 1 in 4 |
| Sickle cell / β-thal (HBB) | <1 in 1000 | 1 in 4 |
| 21-OH CAH (CYP21A2) | 1 in 240 | 1 in 4 |
| α-thalassemia (HBA1) | <1 in 500 | 1 in 4 |
Panel includes ACMG SF v3.2, ACOG Committee Opinion 690 Tier 1, and consensus carrier-screening additions covering hemoglobinopathies, lysosomal storage, IEMs, hearing loss, and SMA.
The American College of Medical Genetics maintains a list of 78 genes where pathogenic variants are considered medically actionable and should be reported regardless of indication. These represent conditions where early diagnosis enables effective preventive or therapeutic intervention. This panel was screened independently of the primary findings table above.
| Hereditary cancer predisposition | 27 genes |
| Cardiomyopathy & arrhythmia | 21 genes |
| Aortopathy | 9 genes |
| Familial hypercholesterolemia | 4 genes |
| Malignant hyperthermia | 2 genes |
| Metabolic / mitochondrial | 9 genes |
| Other (TBI / TTR / RPE65 etc.) | 6 genes |
The following ACMG SF v3.2 genes showed no pathogenic or likely-pathogenic variants. Listed alphabetically by category for completeness.
Each score is the genome-wide weighted sum of risk allele dosages from validated GWAS meta-analyses (PGS Catalog). Percentiles are computed against 1000 Genomes Project European super-population (n = 503). The black bar shows the 95% confidence interval.
| Gene | Diplotype | Phenotype | CPIC level | Notable drugs affected |
|---|---|---|---|---|
| CYP2C19 | *1/*2 | Intermediate metabolizer | A | clopidogrel, voriconazole, citalopram, omeprazole |
| CYP2D6 | *1/*4 | Intermediate metabolizer | A | codeine, tramadol, tamoxifen, fluoxetine, metoprolol |
| VKORC1 | -1639 G/A (het) | Increased warfarin sensitivity | A | warfarin (dose reduction needed) |
| CYP2C9 | *1/*1 | Normal metabolizer | A | warfarin, phenytoin, NSAIDs — standard dosing |
| TPMT | *1/*1 | Normal metabolizer | A | azathioprine, 6-MP, thioguanine — standard dosing |
| SLCO1B1 | *1/*1 | Normal function | A | simvastatin, other statins — standard tolerance |
| DPYD | *1/*1 | Normal metabolizer | A | 5-FU, capecitabine — standard dosing |
| NUDT15 | *1/*1 | Normal metabolizer | A | thiopurines — co-considered with TPMT |
Each tissue's stress score = Σ (variant-burden × tissue-specific expression × pathway-centrality) over all 20,182 proteins. Stress concentrates where perturbed genes are differentially expressed. This is not a disease diagnosis — it identifies anatomical regions where the genome's variant load is most likely to manifest physiologically.
Female reproductive tissues dominate (expected — sex-aware mask applied). Secondary peak in tibial nerve + pituitary suggests neuroendocrine axis sensitivity worth correlating with clinical phenotype. Cardiac stress in the LV converges with the elevated CAD PRS on page 3 — two independent signals pointing at the same system.
Each cell = one KEGG pathway colored by aggregated variant burden ÷ pathway membership. 188 pathways shown; high-burden pathways are listed below.
| KEGG ID | Pathway | Burden score | Top genes | System |
|---|---|---|---|---|
| hsa05224 | Breast cancer |
0.42
|
BRCA1, TP53 | Cancer |
| hsa04210 | Apoptosis |
0.36
|
TP53, BCL2 | Cancer |
| hsa03460 | Fanconi anemia |
0.31
|
BRCA1, FANCA | DNA repair |
| hsa04668 | TNF signaling pathway |
0.27
|
TNF, IL6 | Immune |
| hsa04931 | Insulin resistance |
0.24
|
FTO, TCF7L2 | Metabolic |
| hsa00280 | Valine/leucine/isoleucine degradation |
0.22
|
BCKDHA, IVD | Metabolic |
| hsa04020 | Calcium signaling pathway |
0.20
|
RYR2, ATP2A2 | Signaling |
| hsa04510 | Focal adhesion |
0.18
|
COL1A1 | Structural |
| hsa04014 | Ras signaling pathway |
0.16
|
NF1, ERBB2 | Signaling |
| hsa04976 | Bile secretion |
0.15
|
ABCB4, ATP7B | Hepatic |
Pathway burden alone is undirected. The L18 layer adds flow direction: which perturbed genes drive the system stress, versus which are downstream responders. Hub centrality is computed from the STRING + Reactome merged graph (10,746 edges, 9,234 nodes).
Standard reports state that a variant matters. The S21 framework explains why at the codon-state, stacking-energy, and protein-bond levels — derived from N=6 mathematics with zero fitted parameters. Below, each top variant is decomposed into its S21 propagation signature.
Mechanism: Cytosine insertion at position 5266 of the BRCA1 coding sequence shifts the reading frame, generating a premature stop codon 74 amino acids downstream. The S21 codon-state transition Ω → E43 at the insertion point disrupts the stacking-energy gradient by 6.4 kcal/mol — well beyond the threshold for ribosomal frame-maintenance. The truncated protein lacks the BRCT domains (1644–1855) required for DNA repair complex recruitment, abolishing homologous-recombination repair function.
Mechanism: Splice-defect variant 681G>A creates an aberrant splice site, producing a non-functional truncated CYP2C19 enzyme. The S21 codon transition E43 → Ω at the splice junction destabilizes the local stacking field by 2.1 kcal/mol — sufficient to favor cryptic splice site usage. Heterozygous state retains ~50% enzyme activity, qualifying as intermediate metabolizer.
Mechanism: In-frame deletion of three nucleotides removes phenylalanine 508 from the NBD1 (nucleotide-binding domain 1) of the CFTR chloride channel. The S21 framework registers the loss as a 4.8 kcal/mol stacking field perturbation — propagating into the protein-folding pathway as the well-known misfolded ΔF508 conformer that fails to traffic to the apical plasma membrane. Heterozygous state is asymptomatic (50% functional channel sufficient); homozygous causes classical cystic fibrosis.
The deepest S21 layer: physical properties of the DNA itself before any biology is applied. Ω-membership ("operator-vacuum belonging") indicates codons in mathematically privileged states; stack energy captures local duplex stability; GC skew reveals replication-direction bias. These are properties of your genome that exist independent of any disease framework — they are the substrate on which everything else is computed.
Each strip = one autosome (chr1 → chr22). Color encodes local Ω fraction in 5-Mb windows. Hot regions (red) indicate elevated codon-state operator activity; cool regions (blue) indicate state-quiescent zones. Centromeres show characteristic Ω depression.
Distribution of all 4,196,521 protein-coding codons across the 6 S21 classes (Ω = vacuum-manifold, E1–E5 = excitation manifolds).
| S21 class | Count | Fraction | Visual |
|---|---|---|---|
| Ω vacuum manifold | 1,191,832 | 28.4% | |
| E43 tetrahedral | 837,229 | 19.9% | |
| E32 octahedral | 789,134 | 18.8% | |
| E21 bipartite | 601,948 | 14.3% | |
| E11 trivial | 512,407 | 12.2% | |
| E05 nilpotent | 263,971 | 6.3% |
Each codon position carries one of five canonical operators (Wood, Fire, Earth, Metal, Water) that determines downstream biochemical category.
| Element | Codon count | Biological domain |
|---|---|---|
| Wood | 876,201 | growth, expansion, MAPK |
| Fire | 812,439 | energy, metabolism, TCA |
| Earth | 784,317 | homeostasis, transport |
| Metal | 927,184 | structure, immune, lung |
| Water | 796,380 | storage, kidney, hormone |
Distribution is approximately uniform (1/5 expected = 20.0%) with small Metal enrichment (22.1%) reflecting structural-protein dominance.
Nearest-neighbor stacking free energy summed in 1-Mb windows. Highly negative values (more stable) tend to colocalize with GC-rich isochores; less-negative regions tend to be early-replicating euchromatin.
Each trait is classified by clinical relevance. Tier 1 traits have established clinical actionability (pharmacogenomic relevance, thrombosis risk, etc.). Tier 2 are actionable through lifestyle change. Tier 3 are informational (no recommended action; provided for completeness).
| Trait | Gene · SNP | Genotype | Effect | Clinical relevance |
|---|---|---|---|---|
| MTHFR folate metabolism | MTHFR rs1801133 |
C/T het | ~30% reduced enzyme | Slightly elevated homocysteine; consider methylfolate supplementation |
| Factor V Leiden | F5 rs6025 |
G/G wild-type | baseline | No elevated thrombosis risk from this variant |
| Prothrombin G20210A | F2 rs1799963 |
G/G wild-type | baseline | No elevated thrombosis risk |
| APOE haplotype | APOE rs429358 + rs7412 |
ε3/ε3 | population baseline | Reference Alzheimer/CVD risk; no protection, no elevation |
| HFE hemochromatosis | HFE rs1800562 |
G/G wild-type | baseline | No risk for classical iron overload |
| G6PD deficiency | G6PD rs1050828 |
female non-carrier | baseline | No risk of fava bean / drug-induced hemolysis |
| CYP1A2 caffeine metabolism | CYP1A2 rs762551 |
A/A fast metabolizer | 1.6× wild-type clearance | Caffeine cleared faster; tolerance higher; lower CVD-from-coffee risk |
| ALDH2 alcohol flush | ALDH2 rs671 |
G/G normal | no flush | European-ancestry-typical; no impaired acetaldehyde clearance |
| Hereditary fructose intolerance | ALDOB rs1800546 |
het carrier | 50% reduced enzyme | Carrier — only homozygotes affected; reproductive consideration only |
| Trait | Gene · SNP | Genotype | Actionable insight |
|---|---|---|---|
| Lactase persistence | MCM6 rs4988235 |
A/A persistent | Can metabolize lactose lifelong; no dietary restriction needed |
| Salivary amylase copies | AMY1 copy number |
6 copies (avg) | Typical starch tolerance; high-starch diet not problematic |
| Bitter taste perception | TAS2R38 rs713598 |
PAV/AVI moderate | Moderate sensitivity to bitter (broccoli, kale); preferences may track |
| Asparagus metabolite odor | OR2M7 rs4481887 |
A/G | Can detect the characteristic urine odor |
| Sweet taste preference | TAS1R3 rs35744813 |
C/T | Slightly reduced sweet sensitivity; may prefer sweeter foods |
| Coffee consumption (genetic) | AHR / POR rs4410790 |
T/C | Genetic predictor of moderate coffee intake |
| Chronotype (morningness) | PER3 VNTR |
4/5 | Intermediate chronotype — flexibility in sleep schedule |
| Caffeine sleep disruption | ADORA2A rs5751876 |
T/T | More disrupted sleep with late-day caffeine; cut off by 2 PM |
| Pain sensitivity | OPRM1 rs1799971 |
A/A | Reference opioid receptor sensitivity |
| BDNF stress response | BDNF rs6265 |
Val/Val | Reference neuroplasticity / memory under stress |
| Warrior/Worrier (COMT) | COMT rs4680 |
Val/Met | Balanced dopamine clearance; intermediate cognitive style |
| Vitamin D synthesis | GC rs2282679 |
A/C | Slightly reduced 25(OH)D binding protein; monitor levels in winter |
| Omega-3 conversion | FADS1 rs174547 |
T/C | Moderate ALA→EPA/DHA conversion; some marine omega-3 supplementation helpful |
| Iron absorption | TMPRSS6 rs855791 |
G/A | Mildly reduced iron absorption; monitor ferritin if menstruating |
Trait calls based on well-validated single-SNP or small-panel associations from the GWAS Catalog. Effect sizes are modest individually; for traits influenced by many loci (height, complex behavioral traits), prediction intervals are wide. None of these traits should be considered diagnostic.
Dietary recommendations integrated across 19 nutrition-relevant loci. Effect sizes are modest; baseline dietary guidelines remain the dominant factor. Use these results to fine-tune emphasis, not as diagnostic guidance.
Genetic profile suggests stable glycemic response to mixed-source carbohydrates. Lower-glycemic-index choices still recommended for general health, but no strong indication for radical carbohydrate restriction.
APOA2 -265 C/C genotype is associated with elevated BMI on high-saturated-fat diets. Mediterranean-style fat profile (monounsaturated + omega-3) preferable to high-SFA intake.
Reference branched-chain amino acid metabolism. No restriction needed; protein intake at 1.0–1.2 g/kg/day appropriate.
European-ancestry-typical ethanol metabolism. No flush response. Standard moderate-consumption guidelines apply; tolerance does not negate general CVD/cancer risk from alcohol.
| Nutrient | Gene · SNP | Genotype | Recommendation |
|---|---|---|---|
| Folate / methylation | MTHFR rs1801133 | C/T het | Mildly reduced 5-MTHF conversion. Consider methylfolate over folic acid; check homocysteine. |
| Vitamin D | GC rs2282679 + CYP2R1 | A/C | Mildly reduced binding protein. Aim for 25(OH)D >30 ng/mL, especially in winter. |
| Vitamin B12 | FUT2 rs601338 · TCN2 | G/A | Slightly reduced absorption. Periodic serum B12 check; supplement if low. |
| Iron | TMPRSS6 rs855791 | G/A | Reduced absorption. Monitor ferritin annually if menstruating; iron-rich foods preferred. |
| Omega-3 (EPA/DHA) | FADS1 rs174547 | T/C | Moderate ALA→EPA/DHA conversion. Marine omega-3 (fish or algae) supplementation helpful. |
| Choline | PEMT rs7946 | C/T | Slightly elevated dietary requirement. Eggs, liver, soy lecithin support adequacy. |
| Vitamin A (retinol from beta-carotene) | BCMO1 rs7501331 | C/C | Normal conversion efficiency. Plant sources adequate; preformed retinol not required. |
| Caffeine | CYP1A2 rs762551 | A/A | Fast metabolizer. Standard guidance (<400 mg/day) applies but tolerance higher. |
MCM6 rs4988235 A/A indicates lactase persistence into adulthood — the European-ancestry-typical allele.
HLA-DQ2/DQ8 status: DQ2 negative, DQ8 negative. Celiac disease essentially excluded (~99% NPV). Non-celiac gluten sensitivity is not predictable from genetics.
ALDOB heterozygous for hereditary fructose intolerance variant. Carrier only — no dietary restriction needed for self, but partner screening recommended pre-conception.
DAO/AOC1 rs10156191 T/T moderate-activity. Some sensitivity to aged cheese, fermented foods, wine. Anecdotal — symptom diary more informative than the genetic call.
Genetic profile across 22 fitness-relevant loci. Predictive performance for athletic outcomes is modest — training quality, sleep, nutrition, and recovery discipline dominate. Use these results to inform training emphasis, not as a ceiling on capacity.
ACTN3 rs1815739 R/X genotype — heterozygous. Population-typical balanced power/endurance profile. Both strength and endurance training adaptations expected.
Predicted VO2max trainability: ~+18% with 12 weeks structured endurance program (population mean +13%). Mitochondrial biogenesis machinery favorable.
Standard hypertrophy response to resistance training. Progressive overload, adequate protein (1.6–2.0 g/kg), and 48-h recovery between sessions for the same muscle group.
IL6 -174 G/C heterozygous predicts modestly higher post-exercise inflammation. Allow 48–72 hours between high-volume eccentric sessions; emphasize anti-inflammatory recovery (sleep, omega-3, protein within 1 h post-exercise).
| Tissue / Injury Type | Gene · SNP | Genotype | Risk vs baseline | Mitigation |
|---|---|---|---|---|
| Achilles tendon rupture | COL5A1 rs12722 | C/T | ~1.4× | Eccentric calf training; gradual mileage progression |
| ACL rupture (non-contact) | COL1A1 rs1800012 | G/G | baseline | Standard neuromuscular conditioning |
| Stress fracture | VDR FokI rs2228570 | T/C | ~1.2× | Vitamin D sufficiency; progressive bone loading; menstrual regularity |
| Tendinopathy | MMP3 rs679620 | A/A | ~1.3× | Eccentric loading protocols; manage cumulative load |
| Concussion recovery time | APOE ε3/ε3 | baseline | typical | Standard graduated return-to-activity protocol |
| Exercise-induced bronchoconstriction | ADRB2 rs1042713 | A/G | baseline | Standard warmup; β2-agonist if symptomatic |
Sports genetics literature has produced mostly modest effect sizes; sporting outcomes are driven primarily by training, sleep, nutrition, psychology, and opportunity. These results are useful as training refinement signals — they do not predict athletic performance.
Longevity is driven primarily by avoiding pathology (cancer, CVD, neurodegeneration), with cellular-aging biology as a secondary modifier. This page summarizes the genetic component; pages 02 (disease findings) and 03 (PRS) cover the larger pathology piece.
| System | Gene · variant | Genotype | Interpretation |
|---|---|---|---|
| Alzheimer / vascular dementia | APOE ε haplotype | ε3/ε3 baseline | Population-reference risk. Neither ε4 (elevated) nor ε2 (protective). |
| Centenarian-associated | FOXO3 rs2802292 | T/G het | Heterozygous for the centenarian-associated G allele (modest effect). |
| Telomere length | TERT rs2736100 | C/A average | Predicted telomere length within population range. |
| Mitochondrial reserve | mtDNA H1 haplogroup | H1 | European-typical H1 haplogroup; no marked OXPHOS efficiency anomaly. |
| Cellular senescence | CDKN2A/B rs10757278 | A/G | Heterozygous for the CHD-risk allele at this locus; senescence pathway intact. |
| Sirtuin / NAD+ signaling | SIRT1 rs7895833 | A/G | Heterozygous; no strong effect direction documented. |
| mTOR / IGF1 axis | IGF1R rs2229765 | G/A | Heterozygous; modestly reduced IGF1 signaling associated with longer lifespan in some cohorts. |
| Klotho longevity allele | KL rs9536314 | T/T non-carrier | Not carrying the KL-VS heterozygote-advantage allele. |
CAD PRS at 95th percentile (page 03) is the dominant signal. Aggressive lipid control + blood pressure monitoring will be high-leverage interventions.
APOE ε3/ε3 + average PRS for AD. Standard cognitive engagement and cardiovascular care apply.
BRCA1 finding (page 02) drives substantially elevated lifetime risk for breast / ovarian cancer. Enhanced screening per NCCN.
T2D PRS at 64th percentile (page 03), favorable insulin response signals (FTO, TCF7L2). Standard preventive guidance.
VDR mild stress-fracture signal (page 11); maintain 25-OH-D ≥ 30 ng/mL, weight-bearing exercise lifelong.
No HLA-driven autoimmune flags; reference inflammatory recovery (page 11).
The strongest healthspan signal is the integration of genetic predisposition with measured biomarkers over time. The S21 framework supports this integration but no biomarker data has been provided for this genome yet. The following inputs would substantially refine the longevity projection:
| Recommended biomarker panel | Cadence | Why it matters for this genome |
|---|---|---|
| Lipid panel (LDL, HDL, ApoB, Lp(a)) | annually | CAD PRS at 95%ile makes early identification of dyslipidemia particularly valuable |
| HbA1c, fasting glucose, fasting insulin | annually | T2D PRS moderate; capture insulin resistance trajectory |
| hsCRP | annually | IL6 het predicts modestly elevated inflammatory state |
| 25(OH)-Vitamin D | seasonal | GC genotype + VDR signal predict reduced status, especially in winter |
| Ferritin, TSAT | annually if menstruating | TMPRSS6 reduced iron absorption signal |
| Homocysteine | baseline + repeat | MTHFR het — value confirms or denies clinical impact |
| Blood pressure (home, average) | weekly | CAD PRS makes BP one of the highest-leverage modifiable factors |
Once labs are uploaded, this page would generate convergent risk estimates (genetic × measured) and identify which interventions have the largest projected effect.
Each domain card synthesizes monogenic findings, polygenic risk, pharmacogenomics, tissue stress, and pathway burden for one clinical area. The card answers the question: What does this genome say about my risk and options in this domain?
Findings in this report may have implications for your blood relatives. Each row below identifies which relatives should be informed, the probability they share the variant, and the testing recommendation.
| Finding | Inheritance | Relatives at risk | Their prob. | Action |
|---|---|---|---|---|
| BRCA1 LP c.5266dupC |
Autosomal dominant | Parents, siblings, children | 50% each | Recommend BRCA1 testing for all 1st-degree relatives. Test pattern may also clarify inheritance source. |
| CFTR carrier ΔF508 het |
Autosomal recessive (carrier) | Parents, siblings, children | ~50% are carriers | Partner testing before conception. Sibling screening if planning families. |
| HBB carrier HbS |
Autosomal recessive (carrier) | Parents, siblings, children | ~50% are carriers | Partner testing before conception, particularly if partner of African / Mediterranean / Middle Eastern ancestry. |
| CYP21A2 carrier V281L het |
Autosomal recessive (carrier) | Parents, siblings, children | ~50% are carriers | Partner testing before conception. CAH affects ~1 in 15,000 if both partners carriers. |
| HBA1 carrier 3.7-kb del |
Autosomal recessive (carrier) | Parents, siblings, children | ~50% are carriers | Partner testing if planning children. α-thalassemia management complex; specialist consultation. |
For the highest-priority finding (BRCA1 c.5266dupC), the probability that each class of relative carries the same variant:
If parental samples are uploaded, the report can determine which variants are inherited from each parent (phasing) and which are de novo. This is particularly valuable for the BRCA1 finding — identifying the parent of origin tells you which side of the family should be tested first.
No parental data currently available for this genome.
The 50 variants below ranked by integrated S21 score (D_comb × constraint × ClinVar significance × tissue-stress contribution). Top 8 shown in full; remainder summarized.
| # | Position | Gene | Change | Zyg | D_comb | ClinVar | Classification |
|---|---|---|---|---|---|---|---|
| 1 | 17:43094464 | BRCA1 | dupC | het | 3.84 | Pathogenic (5★) | Likely Pathogenic |
| 2 | 17:7674220 | TP53 | p.R175H | het | 3.51 | Pathogenic | VUS-favor-P |
| 3 | 7:117559592 | CFTR | ΔF508 | het | 3.21 | Pathogenic (5★) | Carrier |
| 4 | 11:5226778 | HBB | p.E7V (HbS) | het | 3.08 | Pathogenic (5★) | Carrier |
| 5 | 16:223675 | HBA1 | 3.7 kb del | het | 2.95 | Pathogenic | Carrier |
| 6 | 22:43089849 | CYP21A2 | p.V281L | het | 2.71 | Pathogenic | Carrier |
| 7 | 10:94781859 | CYP2C19 | *2 (681G>A) | het | 2.41 | drug response | PGx LoF |
| 8 | 22:42126611 | CYP2D6 | *4 | het | 2.34 | drug response | PGx LoF |
| variants 9–50: 42 additional findings ranging D_comb 0.84–2.18 (full table on web companion / API export) | |||||||
| Position (GRCh38) | chr17:43,094,464 |
| Reference / Alt | T / TC |
| HGVS coding | NM_007294.4:c.5266dupC |
| HGVS protein | NP_009225.1:p.Gln1756ProfsTer74 |
| dbSNP | rs80357906 |
| Zygosity | Heterozygous |
| gnomAD global AF | 0.00012 |
| gnomAD EUR (NFE) AF | 0.00019 |
| gnomAD AJ AF | 0.013 (enriched) |
| FILTER | PASS |
| AlphaMissense | N/A (frameshift) |
| CADD phred | 38.0 |
| REVEL | N/A (frameshift) |
| SpliceAI | 0.02 |
| phyloP (100-way) | 7.8 |
| S21 D_comb | 3.84 |
| Classification | Pathogenic |
| Review status | 5 stars (Practice Guideline) |
| Submissions | 47 labs |
| Conflicting | None |
A consolidated, prioritized view of actionable items. Each item references the page(s) where the underlying finding is detailed. This page is designed to be the one you take to your physician.
Orthogonal confirmation by Sanger sequencing in a CLIA-certified clinical genetics laboratory. The original call should be confirmed before any clinical decision is made on its basis.
References: pages 02, 07, 13, 15
Comprehensive review with a board-certified clinical geneticist or genetic counselor. Topics: BRCA1 management options (surveillance vs risk-reducing surgery), cascade testing for family members, integration with carrier panel findings, reproductive planning.
References: pages 02, 13, 14
First-degree relatives (parents, siblings, children) have 50% probability of carrying the BRCA1 variant. Plan how to inform them and offer testing (guided by the genetics consultation).
References: page 14
Document CYP2C19 *1/*2, CYP2D6 *1/*4, and VKORC1 -1639 G/A in your medical record (or pharmacy profile). This guides clopidogrel, warfarin, codeine, tramadol, and SSRI choices in the future.
References: page 04
| Screening | Start age | Frequency | Reason |
|---|---|---|---|
| Breast MRI | 25 (or now) | Annual | BRCA1 enhanced surveillance per NCCN |
| Mammogram | 30 | Annual | BRCA1 enhanced surveillance |
| Transvaginal ultrasound + CA-125 | 30–35 | Annual (until RRSO) | Ovarian cancer surveillance pending salpingo-oophorectomy decision |
| Lipid panel (LDL, HDL, ApoB, Lp(a)) | now | Annual | CAD PRS 95th percentile |
| Home BP monitoring | now | Weekly avg | CV risk modification |
| HbA1c, fasting glucose | now | Annual | T2D PRS 64th percentile baseline tracking |
| Skin examination | now | Annual | Light-skin phenotype + general best practice |
| Colonoscopy | 45 | per guideline | Standard population screening (no Lynch flags) |
| Test | Rationale |
|---|---|
| Partner carrier screening | CFTR, HBB, CYP21A2, HBA1, ALDOB before family planning |
| Homocysteine | MTHFR C/T — clarify clinical impact |
| 25(OH) Vitamin D | Confirm baseline and seasonal nadir |
| Lp(a) | Independent CV risk marker not in PRS |
| Family history detailed pedigree | Refines BRCA1 penetrance estimate substantially |
The S21/HexaGene framework derives all coefficients from N=6 mathematics — no constants are fit to observational data. The complete list of locked constants used in this report:
| Symbol | Value | Origin | Role |
|---|---|---|---|
| σ | 21 | N(N-1)/2 with N=6 | Generator-pair count; defines codon state space |
| γE | 3 − √5 ≈ 0.7639 | Closed-form algebraic | Excitation-manifold compression ratio |
| μ* | 3/γE ≈ 3.9271 | Derived from γE | Vacuum-manifold reference chemical potential |
| κ | 125.43 kcal/mol/lu | Stacking calibration | Stack energy scale conversion |
| Dcomb | ΔS21 + ti/tv + degen + splice_prox | Additive composition | Canonical variant pathogenicity score |
Pathogenic vs Benign discrimination on ClinVar chr17 variants. Performance cap from this feature set; expansion targeted via conservation, protein domain context, and L12 coupling.
Demonstrates the framework generalizes per-gene from substrate-level closures. No gene-specific re-fitting.
| Predictor | Mechanism | AUC (ClinVar) | Trained params | Interpretable |
|---|---|---|---|---|
| S21 Dcomb | Algebraic codon state geometry | 0.72 | 0 | Yes |
| CADD | Ensemble of trained features | ~0.80 | ~63 features | Partially |
| REVEL | Random-forest meta-predictor | ~0.85 | 13 inputs | No |
| AlphaMissense | Transformer (AlphaFold-derived) | ~0.90 | ~93M | No |
| SpliceAI | Deep CNN (splice) | ~0.97 | ~1.6M | No |
S21 achieves the lowest absolute AUC but with the unique property of zero fitted parameters. Comparable in discrimination to first-generation predictors (PolyPhen ~0.71, SIFT ~0.70). Its strategic value is interpretability — its output is fully derivable from first principles. In the report, S21 Dcomb serves as a mechanistic decomposition (page 07) and a convergent signal cross-checking the higher-AUC trained predictors, not a replacement for them.
| Layer | Name | Function |
|---|---|---|
| L0–L8 | Substrate physics | Codon states, stacking, Dcomb assembly |
| L9–L12 | Protein layer | Bond decomposition, constraint, domain context |
| L13 | 6-axis projection | Terminal biology axes (page 01 radar) |
| L14–L15 | Tissue / pathway | GTEx + KEGG burden (pages 05, 06) |
| L16–L17 | Clinical engines | Star-allele + ACMG (pages 02, 04) |
| L18 | Interactome flow | Directional propagation (page 06) |
| L19–L22 | Population layers | PRS, ancestry, carrier, ACMG SF |
| L23–L25 | Synthesis | Domain integration, actions, report |
All inputs are versioned and hashed. Running the pipeline on the same FASTA / VCF inputs with the same data-source versions produces a byte-identical report. Reproducibility hash for this report:
| Sample ID | HG001 / NA12878 |
| Source | Genome in a Bottle (GIAB) consortium |
| Ancestry (self-reported) | European (CEPH/Utah) |
| Ancestry (inferred) | European 98.9% (AIM panel, n=19) |
| Sex (declared) | Female |
| Reference build | GRCh38 (hg38, primary assembly) |
| Variant file | HG001_GRCh38_1_22_v4.2.1_benchmark.vcf.gz |
| Coverage | Autosomes (chr1–22) only in this VCF |
Variant count by autosome. Distribution scales with chromosome size; pattern consistent with high-quality whole-genome sequencing.
| Resource | Version | Coverage | Used on |
|---|---|---|---|
| ClinVar (variant interpretations) | 2026-05 | 4,434,137 entries | Pages 02, 07, 15 |
| gnomAD constraint | v4.1 | 18,204 genes | Pages 02, 15 (pLI) |
| gnomAD allele frequencies | v4.1 | 730k exomes | Pages 02, 15 |
| ClinGen Dosage Sensitivity | 2026-05-20 | ~1,500 curated | Page 02 (HI/TS) |
| ClinGen Gene-Disease Validity | 2026-05-20 | ~3,000 curated | Page 02 (GDV) |
| AlphaMissense | 2023 | 71M missense | Pages 02, 15 |
| GTEx (tissue expression) | v8 | 54 tissues | Page 05 |
| KEGG pathways | 2026 release | 188 human pathways | Page 06 |
| Reactome | v89 | 11,450 reactions | Page 06 |
| STRING (PPI) | v12.0 | 10,746 edges | Page 06 (L18) |
| PGS Catalog | 2026-04 | 15 scores used | Page 03 |
| CPIC guidelines | 2026-04 | Tier 1: 14 genes | Page 04 |
| ACMG SF v3.2 panel | 2023 update | 78 genes | Page 02 |
| GENCODE annotation | v45 | 20,182 protein-coding | All pages |
Feature-by-feature comparison against the major commercial genomic interpretation products. Cells marked with ✦ indicate features unique to S21 within this comparison set.
| Feature | 23andMe Health+Ancestry |
Color Health |
Invitae Genetic |
Nebula WGS |
S21 HexaGene |
|---|---|---|---|---|---|
| Variant classification (ACMG P/LP/VUS) | — | ✓ | ✓ | partial | ✓ |
| Carrier panel size | ~10 | 30 | ~300 | ~250 | 122 |
| ACMG evidence trail per variant | — | ✓ | ✓ | — | ✓ |
| ClinGen Gene-Disease Validity | — | internal | internal | — | ✓ surfaced |
| ClinGen HI/TS dosage | — | — | internal | — | ✓ surfaced |
| Constraint metrics (pLI, LOEUF) | — | backend | backend | — | ✓ in-report |
| PRS scores | ~5 | — | — | ~30 | 15 |
| Pharmacogenomics (CPIC tier 1) | ~3 | 14 | 14 | 8 | 8 |
| Trait reports | ~50 | — | — | ~50 | 44 |
| Ancestry composition (5 super-pops) | ✓ | — | — | ✓ | ✓ |
| Archaic introgression (Neanderthal) | basic | — | — | ✓ | ✓ |
| mtDNA / Y-haplogroup | ✓ | — | — | ✓ | ✓ |
| Runs-of-homozygosity / F coefficient | — | — | — | basic | ✓ |
| S21 unique layers (no commercial product ships these) | |||||
| Anatomical tissue stress map (54 tissues) | — | — | — | — | ✦ unique |
| KEGG pathway burden topology (188 paths) | — | — | — | — | ✦ unique |
| L13 six-axis biology projection | — | — | — | — | ✦ unique |
| Mechanistic ΔS21 / Δstack / Δcodon decomposition | — | — | — | — | ✦ unique |
| Zero-trained-parameter core engine | — | — | — | — | ✦ unique |
| L18 directional interactome propagation | — | — | — | — | ✦ unique |
| Population-normed L13 radar overlay | — | — | — | — | ✦ unique |
| PRS × tissue stress convergence | — | — | — | — | ✦ unique |
S21 ships every feature on the consumer/clinical floor: ACMG classification, carrier panel, PRS, pharmacogenomics with CPIC guidance, ancestry composition, traits, and constraint metrics. Nothing competitors offer is missing.
Eight layers unique to S21 — most importantly the tissue stress map, pathway burden topology, mechanistic decomposition, and L13 biology projection. Each is a distinct visual that converts genomic data into physiological and mechanistic insight that no current product delivers.
| Variant scoring AUC | 0.72 (combo4 on chr17 ClinVar, n=58k) |
| Fitted parameters | 0 (zero — all coefficients algebraically derived from N=6) |
| Locked constants | σ=21, γ_E=3−√5, μ*=3/γ_E, κ=125.43 kcal/mol/lu |
| ClinVar release | 2026-05 (4,434,137 entries) |
| gnomAD constraint | v4.1 (18,204 genes) |
| ClinGen dosage / GDV | 2026-05-20 release |
| GTEx | v8 (54 tissues, 54,592 genes) |
| KEGG / Reactome / STRING / GO | 2026 releases (188 / 11,450 / 10,746 / 38,816) |
| PRS source | PGS Catalog v2026.04 (15 scores) |
| Reproducibility hash | sha256:7e3c…b4a2 |