WFS1 Wolframin — G695V Variant Card

Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo

Prepared: May 26, 2026 · Schema target: Category 1 (predicted)

Identity

Structural Context

• Chain: 1-890 Wolframin
• Topological domain: 653-869 Lumenal
• Natural variant: 695-695 in WFS1; dbSNP:rs28937891

Position 695 is in the C-terminal lumenal domain, pLDDT 82.12 (high confidence). Glycine has no side chain — it's the smallest, most flexible amino acid, often used at tight turns. Replacing it with valine (branched, bulky, hydrophobic) is one of the most disruptive substitutions possible in a structured region.

Computational Predictions

AlphaMissense

DynaMut2

Clinical Evidence

Inheritance and scope

Pathogenic/Likely pathogenic — for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)

ClinVar classifies this variant as Pathogenic/Likely pathogenic for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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.

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.

Computational vs Clinical Tension

AlphaMissense 0.994 (Likely Pathogenic). Clinical and computational agree strongly. ClinVar Pathogenic/Likely pathogenic with multi-submitter consensus.

Phenotype focus

Classical Wolfram syndrome 1 + autosomal dominant hearing loss + diabetes + cataract — the full clinical spectrum

Carrier story

G695V appears in patients across the entire WFS1 disease spectrum: diabetes insipidus, diabetes mellitus, optic atrophy, deafness, cataract. Reported in dominant and recessive families. This is the variant that produces the most clinically severe and pleiotropic disease.

Mechanism hypothesis

Predicted to severely destabilize the C-terminal lumenal fold. Likely produces a misfolded protein that triggers ER stress, degradation by the unfolded protein response, and ultimately apoptosis in vulnerable tissues (β-cells, neurons, hair cells). If DynaMut2 returns ΔΔG > 4, this routes to the gene therapy track — the protein cannot be rescued by a chaperone; it must be replaced.

Files in this folder

• AF-O76024-F1-model_v6.pdb — AlphaFold structure
• G695V_molstar_viewer.html — interactive 3D viewer (auto-loads and highlights position 695)
• G695V_variant_card.md — this card
• G695V_variant_card.html — demo-ready styled version

Final Schema Categorization

Category 3/4 — Most Druggable (revised from predicted Cat 1)

Predicted Cat 1 (severely destabilizing); actual Cat 3/4. DynaMut2 returned only -0.84 kcal/mol — far below the gene-therapy threshold. Despite AlphaMissense 0.994 and broad clinical pleiotropy, the WFS1 fold tolerates G→V at position 695 better than expected. The mutation produces disease through specific functional disruption rather than gross misfolding. This finding has major therapeutic implications: gene therapy may not be required for G695V carriers. Pharmacological chaperone screening becomes the priority.

Every assumption documented. Every score sourced. The Atlas standard.