# WFS1 Wolframin — F439C Variant Card

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

*Phenylalanine → Cysteine at position 439 inside TM4. ClinVar Conflicting including DFNA6 and Wolfram. AlphaMissense 0.886, ΔΔG +0.51 STABILISING.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F439C (p.Phenylalanine439Cysteine) |
| **DNA change** | c.1316T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215388 |
| **Amino acid change** | Phenylalanine (F) → Cysteine (C) — aromatic hydrophobic replaced by thiol-bearing residue. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 439** | **92.75** — well-folded |
| **Domain** | TM4 (427-447), helical transmembrane |
| **Position context** | TM4 (residues 427–447) · position 439 mid-helix (pLDDT 93). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 427-447 Helical

> Position 439 sits in TM4. Neighbors: PHE438 (2.5 Å — second aromatic), THR440 (2.5 Å), THR442 (3.4 Å), THR436 (3.6 Å). Multiple threonines suggest polar packing in the local TM environment.

Replacing F439 with cysteine eliminates aromatic packing. The fold actually stabilises (+0.51) — the local pocket likely accommodates the smaller cysteine more efficiently than the aromatic ring. But AlphaMissense 0.886 + DFNA6 + Wolfram-related clinical evidence confirm severe consequence.

Mechanism is loss of aromatic packing with adjacent F438 plus free-thiol introduction in TM4.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8858** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.51 (Stabilising)** |
| Job ID | 177992458972 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992458972 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/08/18 00:00 |
| Inheritance | DFNA6 hearing loss + WFS1-related disorder documented. |
| WFS1 variant landscape | F439C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)
- Wolfram-like syndrome

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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 3/4 — Most Druggable**

<strong>Category 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +0.51 stabilising. AlphaMissense 0.886 + DFNA6 confirm severe consequence.<br/><br/>Mechanism: lost aromatic packing in TM4 + thiol introduction. Therapeutic: TM4 site-directed.

**Why this card matters.** F439C joins the F-to-C class (with F882C) — both stabilising or near-neutral ΔΔG but pathogenic by AlphaMissense + clinical.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F439C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 439 with ball-and-stick + neighbors within 5Å)
- `F439C_variant_card.md` — this card (source of truth)
- `F439C_variant_card.html` — styled printable card
- `F439C_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)
- `F439C_wildtype_interactions.pse` / `F439C_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.*