# WFS1 Wolframin — A569V Variant Card

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

*Alanine → Valine at position 569 inside TM8. ClinVar Conflicting including Wolfram-like + Cataract 41 + DFNA6. AlphaMissense 0.481 (below threshold), ΔΔG +0.02. AM under-call.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A569V (p.Alanine569Valine) |
| **DNA change** | c.1706C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000504710 |
| **Amino acid change** | Alanine (A) → Valine (V) — small replaced by branched aliphatic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 569** | **73.31** — well-folded |
| **Domain** | TM8 (563-583), helical transmembrane |
| **Position context** | TM8 (residues 563–583) · position 569 mid-helix (pLDDT 73). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 563-583 Helical

> Position 569 in TM8. Neighbors: PHE568 (2.5 Å), LEU570 (2.5 Å), LEU565 (3.3 Å), ILE572 (4.2 Å). Hydrophobic TM environment.

A569V is a conservative volume increase. ΔΔG essentially neutral. AM 0.481 below threshold — under-call. Multi-phenotype (Wolfram-like + Cataract + DFNA6) confirms clinical pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4808** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.02 (Stabilising)** |
| Job ID | 177992470602 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992470602 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/12/24 00:00 |
| Inheritance | Multi-phenotype AD. |
| WFS1 variant landscape | A569V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram-like syndrome
- Cataract 41
- 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).</strong> ΔΔG ≈ 0. AlphaMissense 0.481 below threshold but three documented phenotypes confirm pathogenicity.<br/><br/>Mechanism: subtle volume mismatch in TM8 hydrophobic packing. Therapeutic: TM8 site-directed.

**Why this card matters.** A569V is the first TM8 variant at full v3 depth in the Atlas — new helix target identified.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A569V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 569 with ball-and-stick + neighbors within 5Å)
- `A569V_variant_card.md` — this card (source of truth)
- `A569V_variant_card.html` — styled printable card
- `A569V_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)
- `A569V_wildtype_interactions.pse` / `A569V_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.*