I338V
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialIle→Val p338 loop AM=0.06 ddg=-0.01 pLDDT=66. 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 | F341 | F341 | Preserved |
| Hydrogen bond | A342 | A342 | Preserved |
| Hydrogen bond | Y650 | — | Lost |
| Polar contact | F340 | — | Lost |
| Polar contact | F341 | F341 | Preserved |
| Polar contact | A342 | A342 | Preserved |
| Van der Waals | F340 | — | Lost |
| Van der Waals | — | A342 | Gained |
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 66.25 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", "Inborn genetic diseases". 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 0.063% (57 of 91,058 alleles), 12.2x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (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. |
|---|---|---|---|---|
| South Asian | 0.063% | 57 / 91,058 | 1 | ~1 in 800 |
| East Asian | 0.033% | 15 / 44,846 | 0 | ~1 in 1490 |
| Middle Eastern · under-sampled | 0.017% | 1 / 6,060 | 0 | — |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,504 | 0 | — |
| European (non-Finnish) | 0.00076% | 9 / 1,179,928 | 0 | ~1 in 65550 |
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: ASP339 (2.5 Å — D339N!), THR337 (2.5 Å — T337I!), PHE340 (4.4 Å — TM2 start). Same T337I/D339N cluster. 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 I338V 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.