WFS1 Wolframin — N500K Variant Card

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

Asparagine → Lysine at position 500. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.435, DynaMut2 ΔΔG -0.15 kcal/mol (destabilising).

Identity

Structural Context

UniProt features at this position:

(none catalogued)

Position 500 sits in a transmembrane helix (Transmembrane helix 7). 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 polar amide (asparagine — H-bond donor/acceptor); the mutant is positively charged (lysine — primary amine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

DynaMut2

Clinical Evidence

Inheritance and scope

Uncertain significance — for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant)

ClinVar classifies this variant as Uncertain significance for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.

This rests on a single submitter (1★). Treat the conditions above as submitted, not as documented phenotypes. Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.

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

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 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.15 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.15 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.435. 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
• N500K_molstar_viewer.html — interactive 3D viewer (auto-highlights position 500 with ball-and-stick + neighbors within 5Å)
• N500K_variant_card.md — this card (source of truth)
• N500K_variant_card.html — styled printable card
• N500K_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)
• N500K_wildtype_interactions.pse / N500K_mutant_interactions.pse — PyMOL sessions

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