# WFS1 Wolframin — A465T Variant Card

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

*Alanine → Threonine at position 465. Transmembrane helix 6. ClinVar Uncertain significance, AlphaMissense 0.351, DynaMut2 ΔΔG -1.04 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A465T (p.Alanine465Threonine) |
| **DNA change** | c.1393G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001003765 |
| **Amino acid change** | Alanine (A) → Threonine (T) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 465** | **81.38** — well-folded |
| **Domain** | Transmembrane helix 6 |
| **Position context** | Inside Transmembrane helix 6 · position 465 is bilayer-embedded |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  (none catalogued)

> Position 465 sits in a transmembrane helix (Transmembrane helix 6). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is small/hydrophobic (alanine — methyl sidechain); the mutant is small polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3513** |
| am_class | **ambiguous** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.04 (Destabilising)** |
| Job ID | 178094704852 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094704852 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Uncertain significance** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/07/27 00:00 |
| Inheritance | Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6). |
| WFS1 variant landscape | A465T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Inborn genetic diseases
- Autosomal dominant nonsyndromic hearing loss 6
- Type 2 diabetes mellitus
- Wolfram-like syndrome
- Cataract 41

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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</strong><br/><br/>|ΔΔG|=1.04 negligible. Likely site-specific functional disruption — docking strategy.

**Why this card matters.** Wolframin's fold survives this substitution (|ΔΔG|=1.04 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.351. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A465T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 465 with ball-and-stick + neighbors within 5Å)
- `A465T_variant_card.md` — this card (source of truth)
- `A465T_variant_card.html` — styled printable card
- `A465T_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)
- `A465T_wildtype_interactions.pse` / `A465T_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.*