# WFS1 Wolframin — A48V Variant Card

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

Prepared: May 26, 2026 · Schema target: **Category 5 — IDR EXCLUSION**

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## Identity

| Field | Value |
|---|---|
| **Variant** | A48V |
| **DNA change** | c.143C>T |
| **Gene** | WFS1 |
| **Protein** | Wolframin (890 aa) |
| **UniProt ID** | O76024 |
| **ClinVar accession** | VCV000045435 |
| **Amino acid change** | A → V at position 48 |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 48** | **25.08** |
| **Domain** | N-terminal intrinsically disordered region (1-86) |
| **UniProt features at this position** | |

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Region: 1-86 Disordered

Position 48, pLDDT 25.08. This residue belongs to wolframin's disordered N-terminal region (residues 1–86), annotated by UniProt as the ATP6V1A interaction region but lacking defined secondary structure. AlphaFold's confidence is below the IDR threshold of 50 — meaning the model is essentially a guess about local geometry.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| **am_pathogenicity** | **0.0750** |
| **am_class** | **LBen** |
| **Interpretation** | Likely benign per AlphaMissense |

### DynaMut2
| Field | Value |
|---|---|
| **Job ID** | 177985960542 |
| **ΔΔG (kcal/mol)** | **-0.75 kcal/mol (Destabilising)** |
| **Result URL** | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177985960542 |

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## Clinical Evidence

| Field | Value |
|---|---|
| **ClinVar classification** | **Conflicting classifications of pathogenicity** |
| **Review status** | criteria provided, conflicting classifications |
| **Last evaluated** | 2025/12/20 00:00 |
| **Associated conditions** | Inborn genetic diseases; not specified; not provided; Wolfram syndrome 1 |

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## Computational vs Clinical Tension

AlphaMissense 0.075 (LBen — Likely Benign). ClinVar shows **Conflicting classifications of pathogenicity** — submitting labs cannot agree. Some call it Wolfram syndrome 1; others call it benign. The Atlas resolves this tension by refusing to take a structural position: in an IDR, structure-based predictions are unreliable, and the variant must be triaged to wet-lab functional validation (cell-based assays, family segregation, RNA effects).

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## Phenotype focus

Reported in Wolfram syndrome 1 by some submitters; benign by others — clinical signal unresolved

## Carrier story

A48V is a litmus test for the Atlas's intellectual honesty. It sits at position 48 in the N-terminal intrinsically disordered region, pLDDT 25.08 — deep in the floppy zone where no static model can support reliable structure-function inference.

## Mechanism hypothesis

If DynaMut2 returns any specific ΔΔG, that value is **not trustworthy** for a low-pLDDT residue — DynaMut2 assumes a meaningful starting structure. The correct schema output for A48V is **Category 5 — exclude from druggability prediction; flag for experimental validation only.** This is the Atlas saying 'I don't know — and here's why.'

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A48V_molstar_viewer.html` — interactive 3D viewer (auto-loads and highlights position 48)
- `A48V_variant_card.md` — this card
- `A48V_variant_card.html` — demo-ready styled version



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## Final Schema Categorization

**Category 5 — IDR EXCLUSION (DynaMut2 result is NOT trustworthy)**

DynaMut2 returned a routine-looking -0.75 kcal/mol. **That number should not be used clinically.** The starting AlphaFold structure at position 48 has pLDDT 25.08 — well below the 50 threshold below which the model's local geometry is essentially noise. DynaMut2 assumes a meaningful input structure; for IDR residues that assumption is violated. Combined with AlphaMissense 0.075 (benign) and ClinVar's Conflicting clinical classifications, A48V is the Atlas's textbook 'I don't know — route to wet-lab' case. **The schema's intellectual honesty matters most here.**

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