# WFS1 Wolframin — G831D Variant Card

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

*Glycine → Aspartate at position 831 in wolframin's C-terminal lumenal domain. ClinVar Conflicting. AlphaMissense 0.923, ΔΔG -0.85. Glycine-removal with charge introduction.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G831D (p.Glycine831Aspartate) |
| **DNA change** | c.2492G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000004523 |
| **Amino acid change** | Glycine (G) → Aspartate (D) — smallest amino acid replaced by negatively-charged carboxylate. Loss of backbone flexibility plus charge introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 831** | **78.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 831 (pLDDT 78). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 831-831 in DFNA6; dbSNP:rs28937895

> Position 831 sits in the lumenal domain. Neighbors: ARG832 (2.5 Å — likely salt-bridge partner with new D831!), GLU830 (2.5 Å — adjacent existing carboxylate), LEU833 (4.7 Å), GLU694 (4.8 Å — long-range).

Replacing G831 with aspartate creates a charge cluster: the new D831 carboxylate plus the existing E830, with R832 nearby as potential bridge. The local backbone flexibility is lost; the local electrostatic environment is transformed.

The |ΔΔG| of 0.85 reflects substantial fold cost. AlphaMissense 0.923 confirms severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9226** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.85 (Destabilising)** |
| Job ID | 177992457119 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992457119 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/02/04 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | G831D is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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| = 0.85 — fold survives. AlphaMissense 0.923 confirms severe consequence.<br/><br/>Mechanism: glycine-removal plus charge introduction at the R832-E830 electrostatic environment. Therapeutic: site-directed at the 830-832 microregion.

**Why this card matters.** G831D continues the glycine-removal class — universally pathogenic across the Atlas.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G831D_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 831 with ball-and-stick + neighbors within 5Å)
- `G831D_variant_card.md` — this card (source of truth)
- `G831D_variant_card.html` — styled printable card
- `G831D_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)
- `G831D_wildtype_interactions.pse` / `G831D_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.*