H313Y
Category 4 — Stable Fold, Function DisruptedPathogenic/Likely pathogenicTransmembrane · predictedEditorialHistidine-to-tyrosine substitution at the boundary between the N-terminal cytoplasmic domain and TM1 — borderline pLDDT (57) and a low AlphaMissense (0.167) sit in marked tension with ClinVar Pathogenic/Likely pathogenic, making H313Y a strong candidate for ClinVar reclassification review.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R309 | R309 | Preserved |
| Hydrogen bond | — | A310 | Gained |
| Hydrogen bond | S316 | S316 | Preserved |
| Hydrogen bond | T317 | T317 | Preserved |
| Polar contact | R309 | R309 | Preserved |
| Polar contact | A310 | A310 | Preserved |
| Polar contact | S316 | S316 | Preserved |
| Polar contact | T317 | T317 | Preserved |
| Van der Waals | T317 | T317 | Preserved |
| Hydrophobic | — | T317 | Gained |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
- transmembrane position; predictor benchmarked on soluble proteins
- pLDDT 57.41 below 70
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| East Asian · under-sampled | 0.0025% | 1 / 39,700 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
H313 is held between Met312 (2.44 Angstrom) and Trp314 (2.47 Angstrom). Through-space contacts include Ser316 (3.63 Angstrom), Ala310 (3.92 Angstrom), Arg309 (4.00 Angstrom), Gly311 (4.50 Angstrom), and Leu315 (4.54 Angstrom). Trp314 is structurally striking — a tryptophan at the cytoplasmic edge of TM1 is the classical interfacial-anchor residue, embedding the membrane-helix start at the bilayer interface. The Met312-His313-Trp314 sequence places H313 at a hinge point: a sulfur-bearing residue, an imidazole, and an interfacial aromatic, all within a single short stretch.
Replacing H313 with tyrosine introduces a second large aromatic immediately next to the interfacial Trp314. Two large aromatics in sequence at a membrane interface can either pi-stack productively (potentially stabilizing the transition into TM1) or compete for the interfacial position (destabilizing the Trp314 anchor). DynaMut2 reports DeltaDeltaG = +1.20 kcal/mol — stabilising, larger magnitude than most variants in this batch. The energy function is reading a productive Tyr313-Trp314 aromatic interaction.
AlphaMissense, in striking contrast, scores H313Y at 0.167 — Likely Benign, well below the 0.564 pathogenicity threshold. The discordance with ClinVar Pathogenic/Likely pathogenic is even sharper than for E202G. Possible reconciliations: (a) the variant is genuinely benign and ClinVar's pathogenicity classification was driven by limited evidence that may warrant reclassification; (b) the Atlas's metrics are underweighing a real functional consequence at the cytoplasmic-TM1 boundary; (c) ClinVar evidence reflects compound-heterozygous cases where H313Y is not the causal allele.
The stabilising DeltaDeltaG, the low AM score, and the structurally plausible Tyr-Trp aromatic interaction together suggest the variant may indeed be functionally tolerated. The Atlas should flag H313Y for ClinVar evidence review rather than confidently assign druggability category.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the H313Y PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.