# WFS1 Wolframin — R732H Variant Card

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

*Arginine → Histidine at position 732 in lumenal domain. ClinVar Conflicting including T2D. AlphaMissense 0.386 (below threshold), ΔΔG -0.94. Same position as R732C — second substitution at 732 in the C733-C765 disulfide region.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R732H (p.Arginine732Histidine) |
| **DNA change** | c.2195G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215397 |
| **Amino acid change** | Arginine (R) → Histidine (H) — long positively-charged amine replaced by small titratable aromatic. Charge reduced (pH-dependent). |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 732** | **89.25** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 732 (pLDDT 89). Same as R732C. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 732 same neighbors as R732C: CYS733 (2.5 Å — C733-C765 disulfide cysteine), MET731 (2.5 Å), ASP729 (3.7 Å), GLY728 (3.8 Å).

R732H is the second substitution at R732. Where R732C eliminated charge + introduced thiol, R732H reduces charge to pH-dependent. The C733 disulfide partner is less perturbed than in R732C (no new aberrant thiol).

|ΔΔG| 0.94 + AM 0.386 under-call + T2D confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3859** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.94 (Destabilising)** |
| Job ID | 177992474817 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992474817 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/15 00:00 |
| Inheritance | T2D documented. |
| WFS1 variant landscape | R732H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Type 2 diabetes mellitus

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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| 0.94. AlphaMissense 0.386 below threshold but T2D confirms pathogenicity.<br/><br/>Mechanism: partial charge loss + perturbation of C733 disulfide region from adjacent position. Therapeutic: same C733-C765 microregion as R732C, C733G, C765R, L734H.

**Why this card matters.** R732H joins R732C at position 732 — both at the C733 disulfide-adjacent position. Five Atlas variants now converge on the 732-734 microregion.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R732H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 732 with ball-and-stick + neighbors within 5Å)
- `R732H_variant_card.md` — this card (source of truth)
- `R732H_variant_card.html` — styled printable card
- `R732H_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)
- `R732H_wildtype_interactions.pse` / `R732H_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.*