# WFS1 Wolframin — V288M Variant Card

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

*Valine → Methionine at position 288 in N-terminal cytoplasmic domain. ClinVar Conflicting including DFNA6. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.23. Same position as V288G.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V288M (p.Valine288Methionine) |
| **DNA change** | c.862G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000191322 |
| **Amino acid change** | Valine (V) → Methionine (M) — branched aliphatic replaced by flexible sulfur-containing hydrophobic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 288** | **58.47** — confident |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 288 (pLDDT 58 borderline). Same as V288G. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 288 same neighbors as V288G: VAL289 (2.5 Å), LYS287 (2.5 Å), LEU284 (4.0 Å). Borderline pLDDT.

V288M is the second pathogenic substitution at 288 (with V288G). Conservative chemistry shift. AM 0.13 under-call; DFNA6 confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1315** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.23 (Destabilising)** |
| Job ID | 177992506554 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992506554 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/24 00:00 |
| Inheritance | DFNA6 hearing loss. |
| WFS1 variant landscape | V288M is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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, pLDDT borderline).</strong> |ΔΔG| 0.23. AlphaMissense 0.13 below threshold but DFNA6 confirms.<br/><br/>Mechanism: conservative chemistry shift in borderline-confidence region. Therapeutic: same target as V288G.

**Why this card matters.** V288M + V288G at same position — borderline-region variants both pathogenic.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V288M_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 288 with ball-and-stick + neighbors within 5Å)
- `V288M_variant_card.md` — this card (source of truth)
- `V288M_variant_card.html` — styled printable card
- `V288M_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)
- `V288M_wildtype_interactions.pse` / `V288M_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.*