WFS1 Wolframin — A48V Variant Card

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

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

Identity

Structural Context

• 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.

Computational Predictions

AlphaMissense

DynaMut2

Clinical Evidence

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).

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.'

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

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.

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