# WFS1 Wolframin — V779M Variant Card

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

*Valine → Methionine at position 779 in lumenal domain. ClinVar Conflicting including monogenic diabetes. AlphaMissense 0.399 (below threshold), ΔΔG -0.19. Same position as V779G (Cat 2 outlier)!*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V779M (p.Valine779Methionine) |
| **DNA change** | c.2335G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000045453 |
| **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 779** | **90.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 779 (pLDDT 90). Same as V779G. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 779-779 in DFNA6; benign; dbSNP:rs141328044

> Position 779 same neighbors as V779G: GLY780 (2.4 Å), THR778 (2.5 Å), ARG703 (3.6 Å — R703C!), ILE802 (3.8 Å — I802T!).

V779M is the second pathogenic substitution at the V779 Cat 2 outlier position (with V779G). Where V779G eliminated the side chain entirely (Cat 2), V779M is conservative hydrophobic-to-hydrophobic — fold accommodates more easily (|ΔΔG| 0.19).

AM 0.399 below threshold; multi-phenotype confirms pathogenicity. V779 is structurally critical regardless of substitution.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3991** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.19 (Destabilising)** |
| Job ID | 177992474153 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992474153 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/27 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | V779M is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders
- Monogenic diabetes

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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 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.19. AlphaMissense 0.399 below threshold.<br/><br/>Mechanism: subtle hydrophobic chemistry shift at V779 outlier position. Therapeutic: same V779 microregion as V779G.

**Why this card matters.** V779M + V779G at the Atlas's most-discussed Cat 2 outlier position. Two variants demonstrate V779's structural importance regardless of substitution chemistry.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V779M_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 779 with ball-and-stick + neighbors within 5Å)
- `V779M_variant_card.md` — this card (source of truth)
- `V779M_variant_card.html` — styled printable card
- `V779M_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)
- `V779M_wildtype_interactions.pse` / `V779M_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.*