# WFS1 Wolframin — Y650C Variant Card

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

*Tyrosine → Cysteine at position 650 inside TM10. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.399 (below threshold), ΔΔG +0.31. Third Atlas variant at position 650 (with Y650H, Y650D).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | Y650C (p.Tyrosine650Cysteine) |
| **DNA change** | c.1949A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001218633 |
| **Amino acid change** | Tyrosine (Y) → Cysteine (C) — aromatic phenol replaced by thiol. Loss of aromatic + introduction of disulfide-capable thiol. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 650** | **68.69** — confident |
| **Domain** | TM10 (632-652), helical transmembrane |
| **Position context** | TM10 (residues 632–652) · position 650 (pLDDT 69 borderline). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 632-652 Helical

> Position 650 same neighbors as Y650H/Y650D: PHE649 (2.5 Å), VAL651 (2.5 Å), CYS647 (3.7 Å — C647 already in close contact!), PHE646 (3.7 Å). The C647 contact suggests a potential Y650C-C647 disulfide formation.

Y650C is the THIRD substitution at position 650. The new C650 could potentially form a disulfide with C647 (3.7 Å away) — possibly a beneficial or aberrant chemistry depending on the wild-type C647 state. Compare with Y650H (preserved aromatic) and Y650D (charge introduction).

AM 0.399 below threshold; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3993** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.31 (Stabilising)** |
| Job ID | 177992473973 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992473973 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/10/24 00:00 |
| Inheritance | AD: Cataract + DFNA6. |
| WFS1 variant landscape | Y650C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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**

<strong>Category 4 — Stable Fold, Function Disrupted (AM under-call).</strong> ΔΔG +0.31. AlphaMissense 0.399 below threshold but multi-phenotype confirms pathogenicity.<br/><br/>Mechanism: aromatic loss + potential aberrant disulfide with C647. Therapeutic: same Y650 microregion as Y650H/Y650D.

**Why this card matters.** Y650C completes the Y650 three-substitution series (Y650H, Y650D, Y650C) — position 650 is a multi-substitution hotspot in TM10.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `Y650C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 650 with ball-and-stick + neighbors within 5Å)
- `Y650C_variant_card.md` — this card (source of truth)
- `Y650C_variant_card.html` — styled printable card
- `Y650C_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)
- `Y650C_wildtype_interactions.pse` / `Y650C_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.*