# WFS1 Wolframin — G311D Variant Card

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

*Glycine → Aspartic acid at position 311. Transmembrane helix 1. ClinVar Uncertain significance, AlphaMissense 0.985, DynaMut2 ΔΔG -0.14 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G311D (p.Glycine311Aspartic acid) |
| **DNA change** | c.932G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001477586 |
| **Amino acid change** | Glycine (G) → Aspartic acid (D) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 311** | **62.56** — confident |
| **Domain** | Transmembrane helix 1 |
| **Position context** | Inside Transmembrane helix 1 · position 311 is bilayer-embedded |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  (none catalogued)

> Position 311 sits in a transmembrane helix (Transmembrane helix 1). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is small/flexible (glycine — backbone flexibility, no sidechain); the mutant is negatively charged (aspartate — carboxylate). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9852** |
| am_class | **likely pathogenic** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.14 (Destabilising)** |
| Job ID | 178092091142 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092091142 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Uncertain significance** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2021/08/31 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | G311D is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

(no 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><br/><br/>|ΔΔG|=0.14 < 2 kcal/mol (fold intact) + AlphaMissense 0.985 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

**Why this card matters.** Wolframin's fold survives this substitution (|ΔΔG|=0.14 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.985. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G311D_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 311 with ball-and-stick + neighbors within 5Å)
- `G311D_variant_card.md` — this card (source of truth)
- `G311D_variant_card.html` — styled printable card
- `G311D_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)
- `G311D_wildtype_interactions.pse` / `G311D_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.*