# WFS1 Wolframin — H313Y Variant Card

**Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill**

*Histidine-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.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | H313Y (p.Histidine313Tyrosine) |
| **DNA change** | c.937C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000290817 |
| **Amino acid change** | Histidine (imidazole side chain, pKa ~6, conditionally polar) to Tyrosine (large aromatic phenol, polar hydroxyl, ring system roughly twice the volume of imidazole) at position 313. The substitution exchanges a small polar imidazole for a much larger aromatic phenol. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 313** | **57.41** — confident |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | Position 313 sits at the very C-terminal edge of the N-terminal cytoplasmic domain (residues 87-313) and immediately adjacent to TM1 (residues 314-334). This is a domain-boundary residue, structurally and functionally a transition point. pLDDT 57.41 is borderline — above the IDR exclusion threshold (50) but well below confident folding territory. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> 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.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1671** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **1.2 (Stabilising)** |
| Job ID | 177991407987 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991407987 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/10/06 00:00 |
| Inheritance | Inheritance pattern not explicitly recorded; ClinVar conditions listed as not provided. |
| WFS1 variant landscape | H313Y is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (ClinVar conditions: not provided)

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## Research Path Decision Tree

```
ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking
```

## Final Schema Categorization

**Category 4 — Stable Fold, Function Disrupted**

Final classification: Category 4 — Stable Fold, Function Disrupted (assigned by the schema), with strong metric-discordance flag. The schema's category assignment reflects the DynaMut2 magnitude criterion, but every other metric (low AM score, stabilising DeltaDeltaG, borderline pLDDT, no listed clinical conditions) argues against confident pathogenicity.

For druggability, the right Atlas behavior is to defer therapeutic investment until the ClinVar classification is re-validated. If the variant is genuinely pathogenic, the cytoplasmic-TM1 boundary lesion is potentially small-molecule-accessible. If the variant is benign or a co-segregating bystander, no therapeutic effort is warranted. The clinical-genetics community is increasingly attentive to reclassification of single-submission P/LP variants, and H313Y fits the reclassification-candidate profile.

**Why this card matters.** H313Y is the Atlas's most striking metric-discordant variant in this batch: ClinVar P/LP, but AlphaMissense Likely Benign, DynaMut2 stabilising, borderline pLDDT, and no listed associated conditions. The honest scientific position is that the available evidence does not support confident pathogenicity, and the Atlas should communicate this directly.

This kind of disclosure is precisely the differentiating value of a curated public atlas over an automated database aggregator. The clinical user benefits from knowing that two independent computational pathogenicity predictors and the structural data all argue against a clinical classification that the Atlas is honoring only because ClinVar holds it. Transparency here builds the kind of trust the atlas.rareresearch.ai platform needs to be credible to the rare-disease clinical community.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `H313Y_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 313 with ball-and-stick + neighbors within 5Å)
- `H313Y_variant_card.md` — this card (source of truth)
- `H313Y_variant_card.html` — styled printable card
- `H313Y_dynamut2_summary.html` — clean offline DynaMut2 result card
- `dynamut2_result.json` — structured result data
- `dynamut2_result_page.html` — local snapshot of the Biosig result page (asset URLs absolutized)
- `H313Y_wildtype_interactions.pse` / `H313Y_mutant_interactions.pse` — PyMOL sessions

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*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*