# WFS1 Wolframin — A716T Variant Card

**Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo**

Prepared: May 26, 2026 · Schema target: **Category 4 (predicted)**

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## Identity

| Field | Value |
|---|---|
| **Variant** | A716T |
| **DNA change** | c.2146G>A |
| **Gene** | WFS1 |
| **Protein** | Wolframin (890 aa) |
| **UniProt ID** | O76024 |
| **ClinVar accession** | VCV000004520 |
| **Amino acid change** | A → T at position 716 |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 716** | **83.94** |
| **Domain** | C-terminal lumenal domain (653-869) |
| **UniProt features at this position** | |

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 716-716 in DFNA6; dbSNP:rs28937893

Position 716 sits in the C-terminal lumenal domain, in a well-folded region (pLDDT 83.94). Alanine → Threonine is a small chemical change — adding a polar hydroxyl group where a hydrophobic methyl sat.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| **am_pathogenicity** | **0.2145** |
| **am_class** | **LBen** |
| **Interpretation** | Likely benign — note this disagrees with clinical signal |

### DynaMut2
| Field | Value |
|---|---|
| **Job ID** | 177985952865 |
| **ΔΔG (kcal/mol)** | **-0.8 kcal/mol (Destabilising)** |
| **Result URL** | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177985952865 |

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## Clinical Evidence

| Field | Value |
|---|---|
| **ClinVar classification** | **Pathogenic/Likely pathogenic** |
| **Review status** | criteria provided, multiple submitters, no conflicts |
| **Last evaluated** | 2026/01/24 00:00 |
| **Associated conditions** | Rare genetic deafness; Monogenic hearing loss; not provided |

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## Computational vs Clinical Tension

AlphaMissense scores A716T at **0.2145 (Likely Benign)** — directly contradicting ClinVar's Pathogenic/Likely pathogenic classification supported by multiple independent submitters. This is the most important computational/clinical tension in the entire pilot set, and explains why the Atlas weights clinical evidence above predictions: AlphaMissense is trained primarily on loss-of-function and structure-destabilizing variants. A dominant-negative variant that disrupts oligomeric assembly *without* destabilizing the monomer is precisely the kind of mutation it can miss.

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## Phenotype focus

Autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (DFNA6/14/38)

## Carrier story

A716T is the textbook DFNA6 dominant hearing loss variant — a fundamentally different patient population than classical Wolfram. Onset is in childhood, progression is slow, and the phenotype is almost exclusively cochlear.

## Mechanism hypothesis

Wolframin likely functions as a multimer in the ER membrane. A dominant variant like A716T poisons the multimer by inserting a malformed subunit, even when the monomer fold itself is fine. The schema's Category 4 (stable fold but functional site disrupted) is the right home for this mechanism.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A716T_molstar_viewer.html` — interactive 3D viewer (auto-loads and highlights position 716)
- `A716T_variant_card.md` — this card
- `A716T_variant_card.html` — demo-ready styled version



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## Final Schema Categorization

**Category 4 — Most Druggable (functional disruption with stable fold)**

DynaMut2 confirms the fold is intact (only -0.8 kcal/mol). Combined with A716T's documented dominant pattern of inheritance (DFNA6), this points to a dominant-negative mechanism — the monomer folds, but the multimer assembly is poisoned. AlphaMissense missed this because it's trained on monomer-destabilizing variants. The Atlas catches it via clinical evidence.

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*Every assumption documented. Every score sourced. The Atlas standard.*