R868H

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

Arginine → Histidine at position 868 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Arginine → Histidine at position 868 near the lumenal C-terminus. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.19 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.72. pLDDT 68 borderline.

Interactive 3D Structure

Wild-type reference

Wild-type R868 — hydrogen bond to H872

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DynaMut2 mutant · R868H

Mutant H868 — polar contact contact to H872 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	H872	H872	Preserved
Polar contact	D866	D866	Preserved
Polar contact	H872	H872	Preserved
Aromatic / π	—	H872	Gained
Van der Waals	D866	D866	Preserved
Van der Waals	T870	—	Lost
Van der Waals	H872	H872	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

-0.72kcal/mol

Destabilising — mild

AlphaMissense

0.191

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 conditionsInborn genetic diseases; WFS1-Related Spectrum Disorders

InheritanceWFS1 spectrum.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0077%

cDNA changec.2603G>A

ClinVar accessionVCV000215403

Last evaluated2025/12/10 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 868 near C-terminus. Neighbors: SER869 (2.5 Å), TRP867 (2.5 Å — W867 in TM11 cluster), ASP866 (4.0 Å — D866N region).

R868H sits in the dense 866-876 C-terminal microregion (with D866N, K876T, K862N, E864K). Partial charge loss + perturbed D866 salt-bridge contact. AM 0.19 under-call; multi-phenotype confirms pathogenicity.

Amino-acid chemistry

Arginine (R) → Histidine (H) — charge partial-reduction.

Position in the protein

C-terminal lumenal domain · position 868 (pLDDT 68 borderline).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.72. AlphaMissense 0.19 below threshold but multi-phenotype confirms pathogenicity.

Mechanism: partial charge loss in C-terminal multi-variant cluster. Therapeutic: same 866-876 microregion as D866N, K862N, E864K, K876T.

Why this matters

R868H extends C-terminal cluster — now 6+ variants converging.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R868H 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 R868H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal