L432V
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialLeucine → Valine at position 432 inside TM4 — directly adjacent to E431, the lumenal-membrane hub residue. ClinVar Conflicting including WFS1 spectrum + monogenic diabetes. AlphaMissense 0.38 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.36 kcal/mol (destabilising).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P428 | P428 | Preserved |
| Hydrogen bond | I435 | I435 | Preserved |
| Hydrogen bond | T436 | T436 | Preserved |
| Polar contact | P428 | P428 | Preserved |
| Polar contact | C429 | C429 | Preserved |
| Polar contact | V434 | V434 | Preserved |
| Polar contact | I435 | I435 | Preserved |
| Polar contact | T436 | T436 | Preserved |
| Van der Waals | — | F354 | Gained |
| Van der Waals | P428 | P428 | Preserved |
| Van der Waals | V434 | V434 | Preserved |
| Hydrophobic | F350 | — | Lost |
| Hydrophobic | F354 | F354 | Preserved |
| Hydrophobic | I427 | — | Lost |
| Hydrophobic | P428 | P428 | Preserved |
| Hydrophobic | I435 | — | Lost |
| Hydrophobic | — | T436 | Gained |
| Hydrophobic | I547 | I547 | 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 432 sits at the TM4 lumenal end, immediately downstream of the E431 hub residue. Neighbors: GLU431 (2.5 Å — the multi-variant hub itself), ALA433 (2.5 Å — partner of A433P), CYS429 (3.8 Å). The E431 contact at 2.5 Å is the structurally critical observation: L432V sits in direct contact with the hub that 7+ Atlas variants now converge on (E431Q, S430W, S430L, P428R, A559D, R558C/R558H/A559D microregion).
Replacing L432 with valine is conservative chemistry but the structural cost is substantial — |ΔΔG| 1.36. The wild-type leucine's branched packing supports the precise E431 orientation; reducing the volume to valine shifts the local geometry and perturbs the E431 hub's contact network.
AlphaMissense's 0.38 is below threshold (AM under-call). The multi-phenotype clinical evidence (WFS1 spectrum + monogenic diabetes) plus the substantial ΔΔG confirm pathogenicity. The mechanism is conservative-but-consequential — the type of variant the Atlas's dual-metric framing catches that AM-alone misses.
Druggability Assessment
Mechanism: subtle volume mismatch immediately adjacent to the E431 hub, perturbing E431's contact network. Therapeutic strategy: same E431 hub target as E431Q, S430W, S430L, P428R, A559D.
Why this matters
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