WFS1 Wolframin — G656C Variant Card

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

Glycine → Cysteine at position 656. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.946, DynaMut2 ΔΔG -0.47 kcal/mol (destabilising).

Identity

Structural Context

UniProt features at this position:

(none catalogued)

Position 656 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 small/flexible (glycine — backbone flexibility, no sidechain); the mutant is thiol (cysteine — disulfide-capable, free -SH). 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 — phenotype scope not stated in ClinVar

ClinVar classifies this variant as Uncertain significance, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.

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.

(no conditions catalogued)

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 5 — IDR Exclusion

<strong>Category 5 — IDR Exclusion</strong><br/><br/>pLDDT 48.88 is below 50; DynaMut2 result not trustworthy. Route to wet-lab.

Why this card matters. Position sits in a low-confidence region. Computational stability estimates here are unreliable; this variant needs experimental characterization before any therapeutic strategy is set.

Files in this folder

• AF-O76024-F1-model_v6.pdb — AlphaFold structure
• G656C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 656 with ball-and-stick + neighbors within 5Å)
• G656C_variant_card.md — this card (source of truth)
• G656C_variant_card.html — styled printable card
• G656C_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)
• G656C_wildtype_interactions.pse / G656C_mutant_interactions.pse — PyMOL sessions

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