WFS1 Wolframin — L609Q Variant Card

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

Leucine → Glutamine at position 609. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.489, DynaMut2 ΔΔG -0.16 kcal/mol (destabilising).

Identity

Structural Context

UniProt features at this position:

(none catalogued)

Position 609 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is medium hydrophobic (leucine — branched); the mutant is polar amide (glutamine — 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

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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.16 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.16 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.489. 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
• L609Q_molstar_viewer.html — interactive 3D viewer (auto-highlights position 609 with ball-and-stick + neighbors within 5Å)
• L609Q_variant_card.md — this card (source of truth)
• L609Q_variant_card.html — styled printable card
• L609Q_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)
• L609Q_wildtype_interactions.pse / L609Q_mutant_interactions.pse — PyMOL sessions

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