# WFS1 Wolframin — V839A Variant Card

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

*Valine → Alanine at position 839 in lumenal domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.398 (below threshold), ΔΔG -1.37 (substantial destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V839A (p.Valine839Alanine) |
| **DNA change** | c.2516T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000505203 |
| **Amino acid change** | Valine (V) → Alanine (A) — branched aliphatic replaced by small methyl-bearing. Volume decrease. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 839** | **87.69** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 839 (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 839 in lumenal domain. Neighbors: PHE840 (2.4 Å — partner of L842F, L829P regions), PRO838 (2.5 Å), VAL803 (3.3 Å — long-range; L804P region), TRP837 (4.3 Å).

Replacing V839 with alanine reduces side-chain volume substantially, creating a cavity. The V803 long-range contact through the fold geometry is perturbed. |ΔΔG| 1.37 reflects substantial fold cost. AM 0.398 below threshold; Wolfram 1 confirms pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3978** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.37 (Destabilising)** |
| Job ID | 177992475434 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992475434 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/02/24 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | V839A is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 1.37 substantial. AlphaMissense 0.398 below threshold but Wolfram 1 + ΔΔG confirm pathogenicity.<br/><br/>Mechanism: hydrophobic cavity creation + V839-V803 long-range contact perturbation. Therapeutic: lumenal hub region (with L842F, L829P, L804P targets).

**Why this card matters.** V839A joins the 829-844 lumenal cluster — multiple variants converge.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V839A_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 839 with ball-and-stick + neighbors within 5Å)
- `V839A_variant_card.md` — this card (source of truth)
- `V839A_variant_card.html` — styled printable card
- `V839A_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)
- `V839A_wildtype_interactions.pse` / `V839A_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.*