L592V
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialLeucine → Valine at position 592 inside TM9. ClinVar Conflicting. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.52. pLDDT 63 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | W588 | W588 | Preserved |
| Hydrogen bond | F589 | F589 | Preserved |
| Polar contact | W588 | W588 | Preserved |
| Polar contact | F589 | F589 | Preserved |
| Van der Waals | W588 | — | Lost |
| Van der Waals | — | T590 | Gained |
| Van der Waals | — | K596 | Gained |
| Hydrophobic | W588 | W588 | Preserved |
| Hydrophobic | K596 | K596 | Preserved |
| Hydrophobic | I597 | I597 | Preserved |
| Hydrophobic | T600 | — | Lost |
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
- pLDDT 62.62 below 70
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.
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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 South Asian: AF 0.144% (131 of 91,086 alleles), 16.6x the global figure. The global AF describes the general population, not the at-risk group.
2 homozygotes reported in gnomAD v4 (2 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. |
|---|---|---|---|---|
| South Asian | 0.144% | 131 / 91,086 | 2 | ~1 in 350 |
| Remaining individuals | 0.0080% | 5 / 62,488 | 0 | ~1 in 6250 |
| East Asian | 0.0067% | 3 / 44,892 | 0 | ~1 in 7480 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,606 | 0 | — |
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 592 in TM9. Neighbors: GLU593 (2.4 Å), SER591 (2.5 Å), PHE589 (4.0 Å — TM9 start).
L592V conservative volume reduction in TM9. AM 0.13 under-call; Conflicting clinical evidence.
Druggability Assessment
Mechanism: conservative TM9 volume reduction. Therapeutic: TM9 site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the L592V 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.