# WFS1 Wolframin — G695V Variant Card

**Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo**

Prepared: May 26, 2026 · Schema target: **Category 1 (predicted)**

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## Identity

| Field | Value |
|---|---|
| **Variant** | G695V |
| **DNA change** | c.2084G>T |
| **Gene** | WFS1 |
| **Protein** | Wolframin (890 aa) |
| **UniProt ID** | O76024 |
| **ClinVar accession** | VCV000004510 |
| **Amino acid change** | G → V at position 695 |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 695** | **82.12** |
| **Domain** | C-terminal lumenal domain (653-869) |
| **UniProt features at this position** | |

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 695-695 in WFS1; dbSNP:rs28937891

Position 695 is in the C-terminal lumenal domain, pLDDT 82.12 (high confidence). Glycine has no side chain — it's the smallest, most flexible amino acid, often used at tight turns. Replacing it with valine (branched, bulky, hydrophobic) is one of the most disruptive substitutions possible in a structured region.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| **am_pathogenicity** | **0.9942** |
| **am_class** | **LPath** |
| **Interpretation** | Likely pathogenic — strong signal |

### DynaMut2
| Field | Value |
|---|---|
| **Job ID** | 177985955825 |
| **ΔΔG (kcal/mol)** | **-0.84 kcal/mol (Destabilising)** |
| **Result URL** | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177985955825 |

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## Clinical Evidence

| Field | Value |
|---|---|
| **ClinVar classification** | **Pathogenic/Likely pathogenic** |
| **Review status** | criteria provided, multiple submitters, no conflicts |
| **Last evaluated** | 2025/08/30 00:00 |
| **Associated conditions** | Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram syndrome 1; Wolfram-like syndrome; Cataract 41; not provided |

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## Computational vs Clinical Tension

AlphaMissense 0.994 (Likely Pathogenic). Clinical and computational agree strongly. ClinVar Pathogenic/Likely pathogenic with multi-submitter consensus.

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## Phenotype focus

Classical Wolfram syndrome 1 + autosomal dominant hearing loss + diabetes + cataract — the full clinical spectrum

## Carrier story

G695V appears in patients across the entire WFS1 disease spectrum: diabetes insipidus, diabetes mellitus, optic atrophy, deafness, cataract. Reported in dominant and recessive families. This is the variant that produces the most clinically severe and pleiotropic disease.

## Mechanism hypothesis

Predicted to severely destabilize the C-terminal lumenal fold. Likely produces a misfolded protein that triggers ER stress, degradation by the unfolded protein response, and ultimately apoptosis in vulnerable tissues (β-cells, neurons, hair cells). If DynaMut2 returns ΔΔG > 4, this routes to the gene therapy track — the protein cannot be rescued by a chaperone; it must be replaced.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G695V_molstar_viewer.html` — interactive 3D viewer (auto-loads and highlights position 695)
- `G695V_variant_card.md` — this card
- `G695V_variant_card.html` — demo-ready styled version



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## Final Schema Categorization

**Category 3/4 — Most Druggable (revised from predicted Cat 1)**

**Predicted Cat 1 (severely destabilizing); actual Cat 3/4.** DynaMut2 returned only -0.84 kcal/mol — far below the gene-therapy threshold. Despite AlphaMissense 0.994 and broad clinical pleiotropy, the WFS1 fold tolerates G→V at position 695 better than expected. The mutation produces disease through specific functional disruption rather than gross misfolding. **This finding has major therapeutic implications: gene therapy may not be required for G695V carriers.** Pharmacological chaperone screening becomes the priority.

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*Every assumption documented. Every score sourced. The Atlas standard.*