G695V
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | V659 | V659 | Preserved |
| Hydrogen bond | Y660 | Y660 | Preserved |
| Hydrogen bond | L829 | L829 | Preserved |
| Polar contact | V659 | V659 | Preserved |
| Polar contact | Y660 | Y660 | Preserved |
| Polar contact | L829 | L829 | Preserved |
| Van der Waals | V659 | V659 | Preserved |
| Van der Waals | Y660 | — | Lost |
| Hydrophobic | — | V659 | Gained |
| Hydrophobic | — | Y660 | Gained |
| Hydrophobic | — | I828 | Gained |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Observed at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — G695V Variant Card
Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo
Prepared: May 26, 2026 · Schema target: Category 1 (predicted)
Identity
| Field | Value |
|---|---|
| Variant | G695V |
| DNA change | c.2084G>T |
| Gene | WFS1 |
| Protein | Wolframin (890 aa) |
| UniProt ID | O76024 |
| ClinVar accession | VCV000004510 |
| Amino acid change | G → V at position 695 |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 695 | 82.12 |
| Domain | C-terminal lumenal domain (653-869) |
| UniProt features at this position |
- 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
| Field | Value |
|---|---|
| am_pathogenicity | 0.9942 |
| am_class | LPath |
| Interpretation | Likely pathogenic — strong signal |
DynaMut2
| Field | Value |
|---|---|
| Job ID | 177985955825 |
| ΔΔG (kcal/mol) | -0.84 kcal/mol (Destabilising) |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177985955825 |
Clinical Evidence
| Field | Value |
|---|---|
| ClinVar classification | Pathogenic/Likely pathogenic |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/08/30 00:00 |
| Associated conditions | Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram syndrome 1; Wolfram-like syndrome; Cataract 41; not provided |
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 structureG695V_molstar_viewer.html— interactive 3D viewer (auto-loads and highlights position 695)G695V_variant_card.md— this cardG695V_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.
Feed this card to Wolfram Intelligence
Download the G695V PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.