A422V
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialAlanine → Valine at position 422 inside TM3. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.23 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.31 STABILISING.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | S418 | S418 | Preserved |
| Hydrogen bond | — | F419 | Gained |
| Polar contact | — | P346 | Gained |
| Polar contact | S418 | S418 | Preserved |
| Polar contact | K424 | K424 | Preserved |
| Van der Waals | S418 | S418 | Preserved |
| Hydrophobic | P346 | P346 | Preserved |
| Hydrophobic | L347 | L347 | Preserved |
| Hydrophobic | — | F350 | Gained |
| Hydrophobic | I427 | I427 | Preserved |
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 in the general population.
Structural Context
Position 422 at TM3 end. Neighbors: SER423 (2.4 Å), ILE421 (2.5 Å), SER418 (3.7 Å — TM2-TM3 interface, same S418 as F350I).
A422V at the TM3 lumenal end. Conservative volume increase + stabilising ΔΔG. AM 0.23 under-call; multi-phenotype confirms pathogenicity. The S418 cross-helix contact is structurally significant.
Druggability Assessment
Mechanism: TM3-TM2 interface perturbation at S418. Therapeutic: same target as F350I, V412L, V412A.
Why this matters
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