# WFS1 Wolframin — E394V Variant Card

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

*Glutamate → Valine at position 394 in a connecting loop. ClinVar Conflicting including spastic ataxia and DFNA6. AlphaMissense 0.917, ΔΔG +1.18 STABILISING.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E394V (p.Glutamate394Valine) |
| **DNA change** | c.1181A>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000546078 |
| **Amino acid change** | Glutamate (E) → Valine (V) — negatively-charged carboxylate replaced by branched aliphatic hydrophobic. Complete charge loss in a polar environment. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 394** | **82.06** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 394 (pLDDT 82). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 394 sits in a connecting loop. Neighbors: VAL395 (2.5 Å), ALA393 (2.5 Å), VAL390 (3.8 Å), GLU391 (3.8 Å — second nearby glutamate).

The wild-type E394 with nearby E391 forms a charge cluster in this loop. Replacing E394 with valine eliminates one of two negative charges; the variant fold packs more efficiently with valine in the surrounding hydrophobic environment (V395, V390, A393), producing stabilising ΔΔG of +1.18.

Yet AlphaMissense 0.917 + spastic ataxia + DFNA6 clinical evidence confirm severe consequence. The mechanism is loss of the negatively-charged surface that the wild-type E394 contributed to — partner-recognition disruption despite structural gain.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9166** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **1.18 (Stabilising)** |
| Job ID | 177992457291 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992457291 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/26 00:00 |
| Inheritance | Spastic ataxia and DFNA6 documented. |
| WFS1 variant landscape | E394V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Spastic ataxia
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +1.18 stabilising. AlphaMissense 0.917 + multi-phenotype confirm severe consequence.<br/><br/>Mechanism: loss of E394 charge from the local surface patch. Therapeutic: recognition-surface site-directed.

**Why this card matters.** E394V joins the growing stabilising-but-pathogenic class. Pattern is consistent: charge-loss variants where fold tightens but partner recognition fails.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E394V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 394 with ball-and-stick + neighbors within 5Å)
- `E394V_variant_card.md` — this card (source of truth)
- `E394V_variant_card.html` — styled printable card
- `E394V_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)
- `E394V_wildtype_interactions.pse` / `E394V_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.*