# WFS1 Wolframin — R685H Variant Card

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

*Arginine → Histidine at position 685 — SAME position as R685P (Atlas card flagship pathogenic-stabilising variant) and R685C. ClinVar Conflicting with broad spectrum — Wolfram, Cataract 41, DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.18 (substantial).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R685H (p.Arginine685Histidine) |
| **DNA change** | c.2054G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215395 |
| **Amino acid change** | Arginine (R) → Histidine (H) — long positively-charged amine replaced by smaller titratable aromatic. |

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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, R685C. |
| **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/R685C: THR686 (2.5 Å), ALA684 (2.5 Å — A684T/V/G), ASN682 (3.5 Å), MET683 (4.3 Å), GLN687 (4.4 Å — Q687H).

R685H is the THIRD substitution at position 685 (with R685P, R685C). Partial charge reduction. |ΔΔG| 1.18 substantial; AM 0.12 under-call; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1200** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.18 (Destabilising)** |
| Job ID | 177992507734 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992507734 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/08/09 00:00 |
| Inheritance | Broad multi-phenotype. |
| WFS1 variant landscape | R685H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- 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 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 1.18 substantial. AlphaMissense 0.12 below threshold but THREE phenotypes + substantial ΔΔG confirm pathogenicity.<br/><br/>Mechanism: partial charge loss in the dense 684-688 cluster. Therapeutic: same cluster target as R685P, R685C, A684T/V/G, Q687H.

**Why this card matters.** R685H is the THIRD substitution at position 685. The 684-688 cluster now contains 7+ variants — densest hub in the Atlas.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R685H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 685 with ball-and-stick + neighbors within 5Å)
- `R685H_variant_card.md` — this card (source of truth)
- `R685H_variant_card.html` — styled printable card
- `R685H_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)
- `R685H_wildtype_interactions.pse` / `R685H_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.*