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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in East Asian: AF 0.872% (391 of 44,860 alleles), 33.4x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (1 East Asian). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| East Asian | 0.872% | 391 / 44,860 | 1 | ~1 in 57 |
| Remaining individuals | 0.018% | 11 / 62,502 | 0 | ~1 in 2840 |
| South Asian | 0.0099% | 9 / 91,058 | 0 | ~1 in 5060 |
| Admixed American | 0.0033% | 2 / 60,022 | 0 | ~1 in 15010 |
| African / African American | 0.0027% | 2 / 75,018 | 0 | ~1 in 18750 |
| European (non-Finnish) | 0.00051% | 6 / 1,180,020 | 0 | ~1 in 98330 |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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 and WFS1 spectrum does not resolve it (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: cavity creation in TM3 + F408 cross-helix disruption. Therapeutic: same TM3-TM7 interface as V412L.
Why this matters
Feed this card to Wolfram Intelligence
Download the V412A 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.