# WFS1 Wolframin — R685C Variant Card

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

*Arginine → Cysteine at position 685. ClinVar Conflicting including monogenic diabetes + DFNA6. AlphaMissense 0.581, ΔΔG +0.10. Same position as R685P (Atlas card). R→C class with disulfide-pair partner CYS673 visible nearby in the broader region.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R685C (p.Arginine685Cysteine) |
| **DNA change** | c.2053C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000393391 |
| **Amino acid change** | Arginine (R) → Cysteine (C) — long positively-charged guanidinium replaced by thiol. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 685** | **89.94** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 685 (pLDDT 90). Same as R685P. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 685-685 in DFNA6; dbSNP:rs142668478

> Position 685 same neighbors as R685P: THR686 (2.5 Å), ALA684 (2.5 Å — A684T/V/G cluster), ASN682 (3.5 Å), MET683 (4.3 Å), GLN687 (4.4 Å — Q687H).

R685C is a second pathogenic substitution at 685. Where R685P removed charge + introduced backbone kink, R685C removes charge + introduces free thiol. The new C685 sits in the dense 684-688 cluster — its thiol could engage in disulfide chemistry with other lumenal cysteines.

ΔΔG essentially neutral; AM 0.581 borderline + monogenic diabetes + DFNA6 confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.5811** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.1 (Stabilising)** |
| Job ID | 177992469432 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992469432 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/02/17 00:00 |
| Inheritance | Monogenic diabetes + DFNA6. |
| WFS1 variant landscape | R685C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- 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 3/4 — Most Druggable**

<strong>Category 4 — Stable Fold, Function Disrupted.</strong> ΔΔG ≈ 0. AlphaMissense 0.581 borderline + multi-phenotype confirm pathogenicity.<br/><br/>Mechanism: charge loss + free thiol introduction in dense 684-688 cluster. Therapeutic: same cluster target.

**Why this card matters.** R685C is the FIFTH variant at position 685's microregion (R685P, R685C, A684T/V/G, Q687H). Densest multi-substitution hub in the Atlas.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R685C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 685 with ball-and-stick + neighbors within 5Å)
- `R685C_variant_card.md` — this card (source of truth)
- `R685C_variant_card.html` — styled printable card
- `R685C_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)
- `R685C_wildtype_interactions.pse` / `R685C_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.*