V288G

Category 4 — Stable Fold, Function DisruptedLikely pathogenicCytoplasmic · predictedEditorial

Valine → Glycine at position 288 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Valine → 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

Wild-type reference

Wild-type V288 — hydrogen bond to L284

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DynaMut2 mutant · V288G

Mutant G288 — hydrogen bond contact to L284 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained3 preserved

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

DynaMut2 ΔΔG

-0.23kcal/mol

Destabilising — mild

AlphaMissense

0.480

Amb

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationLikely pathogenic

Review statuscriteria provided, single submitter

Associated conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1 (AR) documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.863T>G

ClinVar accessionVCV003767181

Last evaluated2024/02/27 00:00

Observed at very low frequency in gnomAD.

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.

Amino-acid chemistry

Valine (V) → Glycine (G) — branched aliphatic hydrophobic replaced by smallest amino acid. Loss of side chain entirely.

Position in the protein

N-terminal cytoplasmic domain · position 288 in a borderline-confidence region (pLDDT 58).

Druggability Assessment

Category 3/4 — Most Druggable (AM + pLDDT caveats). |ΔΔG| = 0.23 — fold survives. AlphaMissense 0.480 below threshold but ClinVar Pathogenic + Wolfram 1.

Mechanism is hydrophobic cavity creation. Therapeutic strategy: wet-lab validation before committing to design.

Why this matters

V288G joins the AM-under-call class. The borderline pLDDT and AM signal together make this a wet-lab-priority variant.

Therapeutic Strategy Handoff · prediction

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.

Download V288G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A