V258I
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialVal→Ile p258 N-term AM=0.06 ddg=-0.39 pLDDT=71. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | K253 | K253 | Preserved |
| Hydrogen bond | P260 | P260 | Preserved |
| Polar contact | K253 | K253 | Preserved |
| Carbonyl | — | K253 | Gained |
| Hydrophobic | K253 | K253 | Preserved |
| Hydrophobic | K256 | — | 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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 0.069% (31 of 44,886 alleles), 18.9x 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. |
|---|---|---|---|---|
| East Asian | 0.069% | 31 / 44,886 | 0 | ~1 in 720 |
| Middle Eastern · under-sampled | 0.016% | 1 / 6,062 | 0 | — |
| Remaining individuals | 0.0064% | 4 / 62,480 | 0 | ~1 in 7810 |
| South Asian | 0.0022% | 2 / 91,086 | 0 | ~1 in 22770 |
| European (non-Finnish) | 0.0017% | 20 / 1,180,028 | 0 | ~1 in 29500 |
| Admixed American · under-sampled | 0.0017% | 1 / 60,012 | 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 analysis: ILE259 (2.4 Å), GLY257 (2.5 Å), LYS253 (3.5 Å — same K253 as K252E region). The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the V258I 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.