V288M
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialValine → Methionine at position 288 in N-terminal cytoplasmic domain. ClinVar Conflicting including DFNA6. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.23. Same position as V288G.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L284 | L284 | Preserved |
| Polar contact | L284 | L284 | Preserved |
| Polar contact | — | P292 | Gained |
| Van der Waals | L284 | L284 | Preserved |
| Hydrophobic | A295 | A295 | 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
- pLDDT 58.47 below 70
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 for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); WFS1-related diabetes (autosomal dominant). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- 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 0.033% (2 of 6,084 alleles), 53.1x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Middle Eastern | 0.033% | 2 / 6,084 | 0 | ~1 in 1520 |
| Admixed American | 0.0033% | 2 / 59,972 | 0 | ~1 in 14990 |
| Finnish | 0.0031% | 2 / 64,016 | 0 | ~1 in 16000 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,480 | 0 | — |
| African / African American · under-sampled | 0.0013% | 1 / 74,880 | 0 | — |
| European (non-Finnish) | 0.00017% | 2 / 1,179,960 | 0 | ~1 in 294990 |
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 288 same neighbors as V288G: VAL289 (2.5 Å), LYS287 (2.5 Å), LEU284 (4.0 Å). Borderline pLDDT.
V288M is the second pathogenic substitution at 288 (with V288G). Conservative chemistry shift. AM 0.13 under-call; DFNA6 confirms.
Druggability Assessment
Mechanism: conservative chemistry shift in borderline-confidence region. Therapeutic: same target as V288G.
Why this matters
Feed this card to Wolfram Intelligence
Download the V288M 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.