# WFS1 Wolframin — R676H Variant Card

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

*Arginine → Histidine at position 676 in lumenal domain. ClinVar Conflicting including DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.54.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | R676H (p.Arginine676Histidine) |
| **DNA change** | c.2027G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000426907 |
| **Amino acid change** | Arginine (R) → Histidine (H) — charge partial-reduction. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 676** | **81.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 676 (pLDDT 81). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 676 in lumenal domain. Neighbors: ALA677 (2.5 Å), PRO675 (2.5 Å — adjacent to G674 cluster!), GLY674 (4.0 Å — G674 multi-variant position!).

R676H sits in the dense G674 cluster region. |ΔΔG| 0.54; AM 0.12 under-call; DFNA6 confirms.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1223** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.54 (Destabilising)** |
| Job ID | 177992508941 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992508941 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/07 00:00 |
| Inheritance | DFNA6. |
| WFS1 variant landscape | R676H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

---

## 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| 0.54. AlphaMissense 0.12 below threshold but DFNA6 confirms.<br/><br/>Mechanism: partial charge loss adjacent to G674 cluster. Therapeutic: same G674-R676 microregion.

**Why this card matters.** R676H extends the G674 cluster region — now 5+ variants converge on position 674 ± neighbors.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R676H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 676 with ball-and-stick + neighbors within 5Å)
- `R676H_variant_card.md` — this card (source of truth)
- `R676H_variant_card.html` — styled printable card
- `R676H_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)
- `R676H_wildtype_interactions.pse` / `R676H_mutant_interactions.pse` — PyMOL sessions

---

*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*