R228H

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Arginine → Histidine at position 228 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Arginine → Histidine at position 228 in N-terminal cytoplasmic domain. ClinVar Conflicting including WFS1 spectrum + Wolfram. AlphaMissense 0.20 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.17 (substantial destabilising).

Interactive 3D Structure

Wild-type reference

Wild-type R228 — hydrogen bond to Q224

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DynaMut2 mutant · R228H

Mutant H228 — hydrogen bond to Q224 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost2 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	—	E231	Gained
Hydrogen bond	Q224	Q224	Preserved
Hydrogen bond	K225	K225	Preserved
Hydrogen bond	E231	E231	Preserved
Hydrogen bond	R232	R232	Preserved
Polar contact	Q224	Q224	Preserved
Polar contact	K225	K225	Preserved
Polar contact	—	E231	Gained
Polar contact	R232	R232	Preserved
Van der Waals	Q224	—	Lost
Van der Waals	R232	—	Lost

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

-1.17kcal/mol

Destabilising — moderate

AlphaMissense

0.196

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 conditionsWFS1-Related Spectrum Disorders; Wolfram syndrome 1

InheritanceWFS1 spectrum.

Population frequency (gnomAD v4)Low frequency · AF 0.131%

cDNA changec.683G>A

ClinVar accessionVCV000198190

Last evaluated2026/01/26 00:00

Observed in the general population.

Structural Context

Position 228 in cytoplasmic domain. Neighbors: MET229 (2.5 Å), ARG227 (2.5 Å — adjacent existing arginine!), GLU231 (3.5 Å — likely salt-bridge partner). The R227-R228 double-arginine plus E231 forms a charged surface patch.

R228H reduces charge to pH-dependent. The R227 + H228 pair has different electrostatic character than R227 + R228. |ΔΔG| 1.17 substantial; AM 0.20 under-call; multi-phenotype confirms pathogenicity.

Amino-acid chemistry

Arginine (R) → Histidine (H) — long positively-charged amine replaced by smaller titratable basic.

Position in the protein

N-terminal cytoplasmic domain · position 228 (pLDDT 76).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 1.17 substantial. AlphaMissense 0.20 below threshold but multi-phenotype + substantial ΔΔG confirm pathogenicity.

Mechanism: charge partial-loss from R227-R228-E231 cluster. Therapeutic: cytoplasmic recognition surface site-directed.

Why this matters

R228H continues charge-cluster-loss class in cytoplasmic domain.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R228H 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 R228H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A