R818H

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Arginine → Histidine at position 818 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Arg→His p818 lumenal AM=0.11 ddg=-0.17 pLDDT=86. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type R818 — hydrogen bond to S821

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DynaMut2 mutant · R818H

Mutant H818 — polar contact contact to G820 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F704	F704	Preserved
Hydrogen bond	S821	S821	Preserved
Polar contact	F704	F704	Preserved
Polar contact	G820	—	Lost
Polar contact	S821	S821	Preserved
Van der Waals	F704	F704	Preserved
Van der Waals	S821	S821	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

-0.17kcal/mol

Destabilising — mild

AlphaMissense

0.109

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 0.0074%

cDNA changec.2453G>A

ClinVar accessionVCV000215414

Last evaluated2025/12/18 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: GLN819 (2.4 Å), LEU817 (2.5 Å), SER821 (4.4 Å). Same Q819 long-range contact as R818C, K705N. Multi-variant convergence. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

partial charge reduction

Position in the protein

C-terminal lumenal domain

Druggability Assessment

Cat 3/4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

Why this matters

Same Q819 hub as R818C, K705 region.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R818H 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 R818H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant818–818 · in WFS1; dbSNP:rs35932623