R818H
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArg→His p818 lumenal AM=0.11 ddg=-0.17 pLDDT=86. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| 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
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 at very low frequency in gnomAD.
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). 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
- 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 Middle Eastern: AF 0.033% (2 of 6,038 alleles), 4.5x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (1 South Asian). 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. |
|---|---|---|---|---|
| Middle Eastern | 0.033% | 2 / 6,038 | 0 | ~1 in 1510 |
| East Asian | 0.0089% | 4 / 44,708 | 0 | ~1 in 5590 |
| European (non-Finnish) | 0.0082% | 96 / 1,174,318 | 0 | ~1 in 6120 |
| South Asian | 0.0077% | 7 / 90,802 | 1 | ~1 in 6490 |
| Ashkenazi Jewish | 0.0068% | 2 / 29,410 | 0 | ~1 in 7350 |
| Remaining individuals | 0.0064% | 4 / 62,128 | 0 | ~1 in 7770 |
| African / African American | 0.0040% | 3 / 74,910 | 0 | ~1 in 12490 |
| Admixed American · under-sampled | 0.0017% | 1 / 59,840 | 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 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.
Druggability Assessment
Why this matters
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.