R228H
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialArginine → 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
Bond changes · DynaMut2 interaction analysis
| 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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Retinal dystrophy (inheritance not specified). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Retinal dystrophyinheritance not specifiedsubmitted as: Retinal dystrophy
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.170% (2000 of 1,179,150 alleles), in line with the global figure.
5 homozygotes reported in gnomAD v4 (4 European (non-Finnish); 1 Remaining individuals). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.170% | 2,000 / 1,179,150 | 4 | ~1 in 290 |
| Remaining individuals | 0.103% | 64 / 62,334 | 1 | ~1 in 490 |
| African / African American | 0.032% | 24 / 75,022 | 0 | ~1 in 1560 |
| Admixed American | 0.013% | 8 / 59,752 | 0 | ~1 in 3730 |
| South Asian | 0.010% | 9 / 90,172 | 0 | ~1 in 5010 |
| Finnish | 0.0048% | 3 / 62,854 | 0 | ~1 in 10480 |
| East Asian · under-sampled | 0.0022% | 1 / 44,776 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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 does not resolve it (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: charge partial-loss from R227-R228-E231 cluster. Therapeutic: cytoplasmic recognition surface site-directed.
Why this matters
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.