V503I

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Valine → Isoleucine at position 503 · TM6 (496-516), helical transmembrane · WFS1 (Wolframin)

Val→Ile p503 TM6 AM=0.06 ddg=-0.22 pLDDT=81. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type V503 — hydrogen bond to L506

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DynaMut2 mutant · V503I

Mutant I503 — hydrogen bond contact to L484 lost

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Bond changes · DynaMut2 interaction analysis

0 lost2 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L484	L484	Preserved
Hydrogen bond	L506	L506	Preserved
Hydrogen bond	L507	L507	Preserved
Polar contact	L484	L484	Preserved
Polar contact	C505	C505	Preserved
Polar contact	L506	L506	Preserved
Polar contact	L507	L507	Preserved
Van der Waals	—	L484	Gained
Van der Waals	L506	L506	Preserved
Hydrophobic	L468	L468	Preserved
Hydrophobic	—	L484	Gained
Hydrophobic	F488	F488	Preserved

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

-0.22kcal/mol

Destabilising — mild

AlphaMissense

0.060

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 0.0063%

cDNA changec.1507G>A

ClinVar accessionVCV000215357

Last evaluated2025/09/20 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: SER502 (2.5 Å), PRO504 (2.5 Å — P504L!), CYS505 (4.3 Å — C505Y!). Same TM6 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 branched-aliphatic

Position in the protein

TM6 (496-516)

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

V503I + V503G at same position. TM6 cluster..

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V503I 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 V503I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane496–516 · Helical