# WFS1 Wolframin — C733G Variant Card

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

*Cysteine → Glycine at position 733 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.912, DynaMut2 ΔΔG -1.15 kcal/mol (destabilising). Cysteine-removal variant with potential disulfide partner C765 in spatial proximity.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | C733G (p.Cysteine733Glycine) |
| **DNA change** | c.2197T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001264333 |
| **Amino acid change** | Cysteine (C) → Glycine (G) — thiol-bearing residue replaced by smallest amino acid. Loss of disulfide-bond potential plus loss of side chain entirely. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 733** | **88.50** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 733 in the ER lumen (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 733 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C733 within 5 Å of ARG732 (2.4 Å — same R732 as G736R neighbor), LEU734 (2.5 Å), CYS765 (3.5 Å — possible disulfide partner!), TRP730 (3.7 Å), and ASP729 (4.0 Å).

The C733-C765 distance of 3.5 Å is consistent with a possible disulfide bond in the oxidizing ER lumen. The Atlas's C690R/C690Y cards discuss a similar C673-C690 inferred disulfide; C733-C765 may be a second analogous structural disulfide in the lumenal domain.

Replacing C733 with glycine eliminates this potential disulfide entirely. The fold loses a major structural anchor. The |ΔΔG| of 1.15 reflects this — meaningful destabilization for a single substitution. AlphaMissense's 0.912 + Wolfram 1 clinical evidence confirm severe functional consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9119** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.15 (Destabilising)** |
| Job ID | 177992006242 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992006242 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 1/01/01 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | C733G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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 3/4 — Most Druggable.</strong> |ΔΔG| = 1.15 — fold survives at meaningful cost. AlphaMissense 0.912 + Wolfram 1 confirm severe functional consequence.<br/><br/>Mechanism is loss of an inferred C733-C765 disulfide bond. Therapeutic strategy: site-directed at the C765 partner site, potentially with a small molecule that bridges the two former cysteines.

**Why this card matters.** C733-C765 is the second possible disulfide pair identified in the Atlas (after C673-C690). The lumenal domain appears to use multiple structural disulfides; variants at any of these cysteines disrupt the fold.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `C733G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 733 with ball-and-stick + neighbors within 5Å)
- `C733G_variant_card.md` — this card (source of truth)
- `C733G_variant_card.html` — styled printable card
- `C733G_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)
- `C733G_wildtype_interactions.pse` / `C733G_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.*