# WFS1 Wolframin — E431Q Variant Card

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

*Glutamate → Glutamine at position 431 inside TM4. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.959, DynaMut2 ΔΔG -0.87 kcal/mol (destabilising). The fifth Atlas variant directly involving E431 — the lumenal-membrane hub residue.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E431Q (p.Glutamate431Glutamine) |
| **DNA change** | c.1291G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001027490 |
| **Amino acid change** | Glutamate (E) → Glutamine (Q) — negatively-charged carboxylate replaced by neutral polar amide. Loss of charge; H-bonding preserved. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 431** | **89.81** — well-folded |
| **Domain** | TM4 (427-447), helical transmembrane |
| **Position context** | TM4 (residues 427–447) · position 431 near the lumenal end of TM4 (pLDDT 90). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 427-447 Helical

> Position 431 is the E431 hub residue itself. The AlphaFold model places E431 within 5 Å of LEU432 (2.4 Å), SER430 (2.5 Å — partner of S430W Atlas card), PRO428 (3.6 Å — partner of P428R Atlas card), ALA559 (3.9 Å — partner of A559D Atlas card), and TYR563 (4.0 Å). The neighbor list reads like a roll call of pathogenic Atlas variants — E431 is in spatial contact with the substituted positions in four other Atlas cards.

Replacing E431 with glutamine eliminates the negative charge at this hub position. The salt bridges and electrostatic contacts that E431 maintained with R558 (across the loop) and with S430's hydroxyl and the lumenal interface lose their negative anchor.

The |ΔΔG| of 0.87 reflects substantial fold cost — E431's role is structurally central. AlphaMissense 0.959 + Wolfram syndrome 1 confirm severe functional consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9588** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.87 (Destabilising)** |
| Job ID | 177991929728 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991929728 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2021/01/04 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | E431Q 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 (HUB residue).</strong> |ΔΔG| = 0.87 — fold survives at meaningful cost. AlphaMissense 0.959 + Wolfram 1 confirm severe functional consequence.<br/><br/>E431 is the connective hub residue at the lumenal-TM4-connecting loop boundary. The Atlas now contains 5 variants involving E431 (E431Q this card, A559D, P428R, S430W, plus R558C/R558H/A559D microregion). Drug discovery targeting E431 has multi-variant convergence.

**Why this card matters.** E431Q is the variant AT the hub position — where four other Atlas variants contact in their neighbor analyses. Drug discovery targeting the E431 microregion is the highest-leverage docking site in the WFS1 lumenal-membrane interface region.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E431Q_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 431 with ball-and-stick + neighbors within 5Å)
- `E431Q_variant_card.md` — this card (source of truth)
- `E431Q_variant_card.html` — styled printable card
- `E431Q_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)
- `E431Q_wildtype_interactions.pse` / `E431Q_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.*