I338V

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Isoleucine → Valine at position 338 · Connecting loop · WFS1 (Wolframin)

Ile→Val p338 loop AM=0.06 ddg=-0.01 pLDDT=66. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type I338 — hydrogen bond to A342

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DynaMut2 mutant · I338V

Mutant V338 — hydrogen bond to Y650 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost1 gained4 preserved

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

DynaMut2 ΔΔG

-0.01kcal/mol

Destabilising — mild

AlphaMissense

0.061

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditions(no specific conditions catalogued)

InheritanceConflicting ClinVar classifications.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0051%

cDNA changec.1012A>G

ClinVar accessionVCV001570306

Last evaluated2025/06/13 00:00

Observed at very low frequency in gnomAD.

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.

Amino-acid chemistry

conservative volume reduction

Position in the protein

Connecting loop

Druggability Assessment

Cat 4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

Why this matters

T337I + D339N + I338V cluster.

Therapeutic Strategy Handoff · prediction

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.

Download I338V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin