R383H

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Arginine → Histidine at position 383 · Connecting loop · WFS1 (Wolframin)

Arg→His p383 loop AM=0.08 ddg=-1.35 pLDDT=83. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type R383 — hydrogen bond to N208

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DynaMut2 mutant · R383H

Mutant H383 — hydrogen bond to D379 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost0 gained3 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	N208	—	Lost
Hydrogen bond	D379	—	Lost
Hydrogen bond	L380	L380	Preserved
Polar contact	N208	—	Lost
Polar contact	L380	L380	Preserved
Polar contact	L381	L381	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

-1.35kcal/mol

Destabilising — moderate

AlphaMissense

0.075

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)Low frequency · AF 0.013%

cDNA changec.1148G>A

ClinVar accessionVCV001168671

Last evaluated2025/12/15 00:00

Observed in the general population.

Structural Context

Position analysis: PHE384 (2.4 Å), LEU382 (2.5 Å — L382P!), LEU380 (3.8 Å). Substantial ΔΔG. Adjacent to L382P/E385K cluster. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

partial charge reduction

Position in the protein

Connecting loop

Druggability Assessment

Cat 3/4 — 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

Same 382-385 loop cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R383H 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 R383H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin