V412A
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialValine → Alanine at position 412 inside TM3. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.395 (below threshold), ΔΔG -1.23. Same position as V412L — second substitution at 412.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M357 | M357 | Preserved |
| Hydrogen bond | F408 | F408 | Preserved |
| Hydrogen bond | L409 | L409 | Preserved |
| Hydrogen bond | V415 | V415 | Preserved |
| Hydrogen bond | I416 | I416 | Preserved |
| Polar contact | M357 | — | Lost |
| Polar contact | F408 | F408 | Preserved |
| Polar contact | L409 | L409 | Preserved |
| Polar contact | F414 | — | Lost |
| Polar contact | V415 | V415 | Preserved |
| Polar contact | I416 | I416 | Preserved |
| Van der Waals | F408 | — | Lost |
| Van der Waals | — | L410 | Gained |
| Van der Waals | F414 | — | Lost |
| Van der Waals | I416 | I416 | Preserved |
| Hydrophobic | M357 | M357 | Preserved |
| Hydrophobic | F408 | — | Lost |
| Hydrophobic | I416 | — | Lost |
| Hydrophobic | M539 | M539 | 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 412 same neighbors as V412L: PHE413 (2.5 Å), SER411 (2.5 Å), LEU409 (3.8 Å), PHE408 (3.9 Å — TM3-TM7 interface position).
V412A is the more drastic substitution at 412 (vs the conservative V412L). Volume loss creates cavity in TM3. The F408 cross-helix contact is perturbed. |ΔΔG| 1.23 substantial. AM 0.395 below threshold but WFS1 spectrum confirms pathogenicity.
Druggability Assessment
Mechanism: cavity creation in TM3 + F408 cross-helix disruption. Therapeutic: same TM3-TM7 interface as V412L.
Why this matters
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