# WFS1 Wolframin — A422V Variant Card

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

*Alanine → Valine at position 422 inside TM3. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.23 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.31 STABILISING.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A422V (p.Alanine422Valine) |
| **DNA change** | c.1265C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000393388 |
| **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 422** | **87.12** — well-folded |
| **Domain** | TM3 (402-422), helical transmembrane |
| **Position context** | TM3 (residues 402–422) · position 422 at TM3 end (pLDDT 87). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 402-422 Helical

> Position 422 at TM3 end. Neighbors: SER423 (2.4 Å), ILE421 (2.5 Å), SER418 (3.7 Å — TM2-TM3 interface, same S418 as F350I).

A422V at the TM3 lumenal end. Conservative volume increase + stabilising ΔΔG. AM 0.23 under-call; multi-phenotype confirms pathogenicity. The S418 cross-helix contact is structurally significant.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.2338** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.31 (Stabilising)** |
| Job ID | 177992497673 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992497673 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/23 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | A422V 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 4 — Stable Fold, Function Disrupted (AM under-call).</strong> ΔΔG +0.31. AlphaMissense 0.23 below threshold but multi-phenotype confirms pathogenicity.<br/><br/>Mechanism: TM3-TM2 interface perturbation at S418. Therapeutic: same target as F350I, V412L, V412A.

**Why this card matters.** A422V continues TM3-TM2 interface convergence.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A422V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 422 with ball-and-stick + neighbors within 5Å)
- `A422V_variant_card.md` — this card (source of truth)
- `A422V_variant_card.html` — styled printable card
- `A422V_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)
- `A422V_wildtype_interactions.pse` / `A422V_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.*