WFS1 Wolframin — C537Y Variant Card

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

Cysteine → Tyrosine at position 537. Transmembrane helix 8. ClinVar Uncertain significance, AlphaMissense 0.986, DynaMut2 ΔΔG -1.43 kcal/mol (destabilising).

Identity

Structural Context

UniProt features at this position:

(none catalogued)

Position 537 sits in a transmembrane helix (Transmembrane helix 8). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is thiol (cysteine — disulfide-capable, free -SH); the mutant is aromatic with hydroxyl (tyrosine — H-bond donor/acceptor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

DynaMut2

Clinical Evidence

• Inborn genetic diseases
• Monogenic diabetes
• Cataract 41
• Autosomal dominant nonsyndromic hearing loss 6
• Type 2 diabetes mellitus
• Wolfram syndrome 1
• Wolfram-like syndrome

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</strong><br/><br/>|ΔΔG|=1.43 < 2 kcal/mol (fold intact) + AlphaMissense 0.986 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.43 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.986. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

• AF-O76024-F1-model_v6.pdb — AlphaFold structure
• C537Y_molstar_viewer.html — interactive 3D viewer (auto-highlights position 537 with ball-and-stick + neighbors within 5Å)
• C537Y_variant_card.md — this card (source of truth)
• C537Y_variant_card.html — styled printable card
• C537Y_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)
• C537Y_wildtype_interactions.pse / C537Y_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.