# WFS1 Wolframin — R703C Variant Card

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

*Arginine → Cysteine at position 703 in lumenal domain. ClinVar Conflicting including Cataract 41 + Wolfram + DFNA6. AlphaMissense 0.471 (below threshold), ΔΔG +0.02. AM under-call with multi-phenotype.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R703C (p.Arginine703Cysteine) |
| **DNA change** | c.2107C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001299576 |
| **Amino acid change** | Arginine (R) → Cysteine (C) — charge loss + thiol introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 703** | **89.44** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 703 (pLDDT 89). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 703-703 in DFNA6; dbSNP:rs1323852277

> Position 703 in lumenal domain near R708 region. Neighbors: PHE704 (2.4 Å — partner of V707F), GLY702 (2.5 Å — G702S!), SER821 (3.4 Å — long-range), GLY780 (3.6 Å — near V779/D801 region).

R703C sits in the dense 702-708 cluster (with G702S, F704, V707F, R708L, R708C). Loss of R703 charge + thiol introduction. ΔΔG essentially neutral; AM 0.471 below threshold; multi-phenotype confirms pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4706** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.02 (Stabilising)** |
| Job ID | 177992470845 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992470845 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/12/15 00:00 |
| Inheritance | Multi-phenotype AD. |
| WFS1 variant landscape | R703C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41
- Wolfram syndrome 1
- 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 0.471 below threshold but three documented phenotypes confirm pathogenicity.<br/><br/>Mechanism: charge loss + thiol in the dense 702-708 cluster. Therapeutic: same multi-variant cluster.

**Why this card matters.** R703C extends the 702-708 multi-variant cluster — six Atlas variants now converge here.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R703C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 703 with ball-and-stick + neighbors within 5Å)
- `R703C_variant_card.md` — this card (source of truth)
- `R703C_variant_card.html` — styled printable card
- `R703C_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)
- `R703C_wildtype_interactions.pse` / `R703C_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.*