# WFS1 Wolframin — F331I Variant Card

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

*Phenylalanine → Isoleucine at position 331 inside TM1. ClinVar Conflicting including DFNA6. AlphaMissense 0.458 (below threshold), ΔΔG +0.56 STABILISING.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F331I (p.Phenylalanine331Isoleucine) |
| **DNA change** | c.991T>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000229648 |
| **Amino acid change** | Phenylalanine (F) → Isoleucine (I) — aromatic replaced by branched aliphatic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 331** | **74.75** — well-folded |
| **Domain** | TM1 (314-334), helical transmembrane |
| **Position context** | TM1 (residues 314–334) · position 331 near TM1 end (pLDDT 75). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 314-334 Helical

> Position 331 near end of TM1. Neighbors: ILE332 (2.5 Å), PHE330 (2.5 Å — adjacent existing phenylalanine), SER334 (3.5 Å), LEU327 (3.6 Å). Aromatic cluster F330-F331.

Replacing F331 with isoleucine eliminates aromatic packing with F330 + lost adjacency. ΔΔG +0.56 stabilising; AM 0.458 under-call; DFNA6 + WFS1 spectrum confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4583** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.56 (Stabilising)** |
| Job ID | 177992471066 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992471066 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/04/08 00:00 |
| Inheritance | DFNA6. |
| WFS1 variant landscape | F331I is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Inborn genetic diseases
- 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, stabilising).</strong> ΔΔG +0.56. AlphaMissense 0.458 below threshold but DFNA6 confirm pathogenicity.<br/><br/>Mechanism: lost F330-F331 aromatic packing in TM1. Therapeutic: TM1 microregion.

**Why this card matters.** F331I extends the TM1 cluster (now 7+ variants in or near TM1).

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F331I_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 331 with ball-and-stick + neighbors within 5Å)
- `F331I_variant_card.md` — this card (source of truth)
- `F331I_variant_card.html` — styled printable card
- `F331I_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)
- `F331I_wildtype_interactions.pse` / `F331I_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.*