# WFS1 Wolframin — A326T Variant Card

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

*Alanine → Threonine at position 326 inside TM1. ClinVar Conflicting including Wolfram + inborn diseases. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.79. Third substitution at position 326 (with A326E, A326V).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A326T (p.Alanine326Threonine) |
| **DNA change** | c.976G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001584586 |
| **Amino acid change** | Alanine (A) → Threonine (T) — small replaced by polar hydroxyl. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 326** | **76.88** — well-folded |
| **Domain** | TM1 (314-334), helical transmembrane |
| **Position context** | TM1 (residues 314–334) · position 326 (pLDDT 77). Same as A326E, A326V. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 314-334 Helical
  - Natural variant: 326-326 in dbSNP:rs369795224

> Position 326 same neighbors as A326E/A326V: ASN325 (2.5 Å), LEU327 (2.5 Å), HIS322 (3.6 Å).

A326T is the THIRD substitution at position 326 (with A326E charge, A326V volume). Position 326 is structurally inflexible regardless of substitution chemistry — three variants confirm this. AM 0.13 under-call; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1278** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.79 (Destabilising)** |
| Job ID | 177992506089 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992506089 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/02/01 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | A326T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Inborn genetic diseases
- 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.79. AlphaMissense 0.13 below threshold but multi-phenotype + three-substitution position confirm pathogenicity.<br/><br/>Mechanism: polarity introduction at structurally critical TM1 position. Therapeutic: same TM1 microregion as A326E, A326V.

**Why this card matters.** A326T completes the THIRD substitution at position 326 — three pathogenic variants establish position 326 as inflexible.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A326T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 326 with ball-and-stick + neighbors within 5Å)
- `A326T_variant_card.md` — this card (source of truth)
- `A326T_variant_card.html` — styled printable card
- `A326T_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)
- `A326T_wildtype_interactions.pse` / `A326T_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.*