V779G
Category 2 — Moderately DestabilizingLikely pathogenicLumenal · predictedσ-1 candidateEditorialValine → Glycine at position 779 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic with the full clinical spectrum documented — Wolfram syndrome 1, Wolfram-like syndrome, type 2 diabetes, cataract 41, and DFNA6 hearing loss. AlphaMissense 0.908, DynaMut2 ΔΔG -2.92 kcal/mol (destabilising).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R703 | — | Lost |
| Hydrogen bond | D801 | — | Lost |
| Hydrogen bond | I802 | I802 | Preserved |
| Polar contact | — | R703 | Gained |
| Polar contact | D801 | — | Lost |
| Polar contact | I802 | I802 | Preserved |
| Carbonyl | — | R703 | Gained |
| Van der Waals | G702 | — | Lost |
| Hydrophobic | I777 | — | Lost |
| Hydrophobic | M781 | — | Lost |
| Hydrophobic | L804 | — | Lost |
| Hydrophobic | I823 | — | Lost |
| Hydrophobic | F825 | — | Lost |
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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 779 lies in wolframin's C-terminal lumenal domain (residues 653–869), the protein's largest soluble region and the primary interface for documented partner interactions with ATF6 and the Na+/K+ ATPase β1 subunit. The AlphaFold model shows V779 packed into a tight local cluster: GLY780 (2.4 Å) and THR778 (2.5 Å) are the immediate sequence neighbors, but the structural context also includes ARG703 (3.6 Å), PHE704 (4.8 Å), and ILE802 (3.8 Å) — residues from elsewhere in the lumenal fold that form a hydrophobic pocket against V779's isopropyl side chain.
Replacing valine with glycine at this position is unusually disruptive because glycine has no side chain. The wild-type contributes branched hydrophobic packing into the local pocket; the mutant removes that volume entirely. The resulting cavity is roughly the size of a methyl group and a methine — small, but structurally significant when the position was contributing to packing density. The backbone gains rotational freedom it did not have before, and the surrounding residues are no longer held in their pre-mutation geometry.
This explains the |ΔΔG| of 2.92 kcal/mol — one of only two variants in the entire 245-variant Atlas to cross the 2 kcal/mol moderate-destabilization threshold. The protein still folds (|ΔΔG| is well below the 4 kcal/mol gross-misfolding line), but the fold is energetically compromised and a fraction of the translated protein will be cleared by ER quality control before reaching its functional location.
Druggability Assessment
This is a pharmacological chaperone candidate. The therapeutic strategy is not site-directed small-molecule design (the perturbation is global to a local fold, not a specific binding pocket) but rather a chaperone that stabilizes the wolframin fold and shifts the folding equilibrium toward functional protein. Analogous to CFTR correctors in cystic fibrosis: rescue the folding yield, not the catalytic site.
The breadth of clinical conditions (five documented phenotypes including both the classical AR Wolfram syndrome and the AD hearing loss pattern) makes this a particularly high-value chaperone target: a single intervention could address multiple clinical presentations across both inheritance modes.
Why this matters
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