WFS1 Wolframin — N325D Variant Card

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

Asparagine → Aspartic acid at position 325. Transmembrane helix 1. ClinVar Uncertain significance, AlphaMissense 0.611, DynaMut2 ΔΔG +0.05 kcal/mol (stabilising).

Identity

Structural Context

UniProt features at this position:

(none catalogued)

Position 325 sits in a transmembrane helix (Transmembrane helix 1). 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 negatively charged (aspartate — carboxylate). 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 WFS1-related spectrum (unresolved mode) (dominant or recessive)

ClinVar classifies this variant as Uncertain significance for WFS1-related spectrum (unresolved mode) (dominant or recessive). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.

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.

• WFS1-related disorder

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|=0.05 < 2 kcal/mol (fold intact) + AlphaMissense 0.611 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|=0.05 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.611. 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
• N325D_molstar_viewer.html — interactive 3D viewer (auto-highlights position 325 with ball-and-stick + neighbors within 5Å)
• N325D_variant_card.md — this card (source of truth)
• N325D_variant_card.html — styled printable card
• N325D_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)
• N325D_wildtype_interactions.pse / N325D_mutant_interactions.pse — PyMOL sessions

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