# WFS1 Wolframin — M731V Variant Card

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

*Met→Val p731 lumenal AM=0.11 ddg=-0.86 pLDDT=85. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | M731V (p.Methionine731Valine) |
| **DNA change** | c.2191A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000374399 |
| **Amino acid change** | methionine chemistry lost |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 731** | **84.56** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position analysis: TRP730 (2.5 Å), ARG732 (2.5 Å — R732C/H!), GLY728 (3.7 Å). Adjacent to R732 multi-variant position and C733-C765 disulfide region. The Atlas's neighbor extraction surfaces this variant's contacts.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1132** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.86 (Destabilising)** |
| Job ID | 177992511572 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992511572 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/05/04 00:00 |
| Inheritance | Conflicting ClinVar classifications. |
| WFS1 variant landscape | M731V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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>Cat 3/4 — see structural prose.</strong> AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

**Why this card matters.** Adjacent to C733-C765 disulfide region.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `M731V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 731 with ball-and-stick + neighbors within 5Å)
- `M731V_variant_card.md` — this card (source of truth)
- `M731V_variant_card.html` — styled printable card
- `M731V_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)
- `M731V_wildtype_interactions.pse` / `M731V_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.*