# WFS1 Wolframin — R732C Variant Card

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

*Arginine → Cysteine at position 732 in lumenal domain. ClinVar Conflicting including monogenic diabetes, Wolfram, T2D. AlphaMissense 0.637, ΔΔG -0.83. Charge loss + thiol near C733-C765 disulfide region.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | R732C (p.Arginine732Cysteine) |
| **DNA change** | c.2194C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215396 |
| **Amino acid change** | Arginine (R) → Cysteine (C) — positively-charged guanidinium replaced by thiol. |

---

## 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). Adjacent to C733 (in C733-C765 disulfide). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 732 sits next to C733 (3.5 Å from C765 in the inferred disulfide). Neighbors: CYS733 (2.5 Å), MET731 (2.5 Å), ASP729 (3.7 Å — partner of G728-D729 region), GLY728 (3.8 Å).

The wild-type R732 is the same R732 referenced as a partner in G736R Atlas card. R732C replaces this critical arginine with a free cysteine — adjacent to C733 (which forms a disulfide with C765). The new C732 could potentially form aberrant disulfide chemistry with C733 itself, disrupting the C733-C765 disulfide entirely.

|ΔΔG| 0.83 + AM 0.637 + multi-phenotype confirm severe consequence.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6371** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.83 (Destabilising)** |
| Job ID | 177992465984 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992465984 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/23 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | R732C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- Wolfram syndrome 1
- Type 2 diabetes mellitus

---

## 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 3/4 — Most Druggable.</strong> |ΔΔG| = 0.83. AlphaMissense 0.637 + multi-phenotype confirm severe consequence.<br/><br/>Mechanism: loss of R732 charge + potential aberrant disulfide with C733 disrupting the C733-C765 structural disulfide. Therapeutic: site-directed at the R732-C733-C765 microregion.

**Why this card matters.** R732C is one of the most dangerous R→C class variants — it sits adjacent to a structural disulfide cysteine, creating a real risk of aberrant disulfide formation that disrupts the wild-type disulfide.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R732C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 732 with ball-and-stick + neighbors within 5Å)
- `R732C_variant_card.md` — this card (source of truth)
- `R732C_variant_card.html` — styled printable card
- `R732C_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)
- `R732C_wildtype_interactions.pse` / `R732C_mutant_interactions.pse` — PyMOL sessions

---

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