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
- 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); WFS1-related diabetes (autosomal dominant); 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
- WFS1-related diabetesautosomal dominantsubmitted as: Monogenic diabetes
- 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 Middle Eastern: AF 1.52% (92 of 6,062 alleles), 4.1x the global figure. The global AF describes the general population, not the at-risk group.
23 homozygotes reported in gnomAD v4 (3 Middle Eastern; 3 Ashkenazi Jewish; 1 Remaining individuals; 15 European (non-Finnish); 1 South 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. |
|---|---|---|---|---|
| Middle Eastern | 1.52% | 92 / 6,062 | 3 | ~1 in 33 |
| Ashkenazi Jewish | 1.47% | 436 / 29,608 | 3 | ~1 in 34 |
| Remaining individuals | 0.520% | 325 / 62,508 | 1 | ~1 in 96 |
| Admixed American | 0.440% | 264 / 60,026 | 0 | ~1 in 110 |
| European (non-Finnish) | 0.395% | 4,663 / 1,180,040 | 15 | ~1 in 130 |
| Amish | 0.219% | 2 / 912 | 0 | ~1 in 230 |
| South Asian | 0.194% | 177 / 91,072 | 1 | ~1 in 260 |
| African / African American | 0.080% | 60 / 75,042 | 0 | ~1 in 630 |
| Finnish | 0.030% | 19 / 63,906 | 0 | ~1 in 1680 |
| East Asian | 0.0045% | 2 / 44,878 | 0 | ~1 in 11220 |
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 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
Feed this card to Wolfram Intelligence
Download the L432V 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.