V288G
Category 4 — Stable Fold, Function DisruptedLikely pathogenicCytoplasmic · predictedEditorialValine → Glycine at position 288 in wolframin's N-terminal cytoplasmic domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.480 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.23 kcal/mol. pLDDT 58 borderline.
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 |
| Van der Waals | L284 | L284 | Preserved |
| Hydrophobic | A295 | — | 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
- 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 Likely pathogenic 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
- This rests on a single submitter (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★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
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. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,962 | 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 288 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places V288 within 5 Å of VAL289 (2.5 Å), LYS287 (2.5 Å), LEU284 (4.0 Å), ALA295 (4.5 Å), and LEU286 (4.5 Å). Mostly hydrophobic environment.
Replacing V288 with glycine removes the branched aliphatic side chain entirely, creating a cavity. The fold absorbs the substitution (|ΔΔG| 0.23 small) — the glycine permits backbone conformations the wild-type valine constrained, possibly compensating somewhat for the lost packing volume.
AlphaMissense's 0.480 is below the threshold — AM under-call. ClinVar Likely Pathogenic + Wolfram 1 establishes clinical pathogenicity. pLDDT 58 is borderline; structural details deserve wet-lab confirmation.
Druggability Assessment
Mechanism is hydrophobic cavity creation. Therapeutic strategy: wet-lab validation before committing to design.
Why this matters
Feed this card to Wolfram Intelligence
Download the V288G 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.