R818C
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArginine → Cysteine at position 818 in lumenal domain. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.38 (below threshold), DynaMut2 ΔΔG +0.24 kcal/mol (mild stabilising). Another R→C class variant with free-thiol risk.
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 | — | Lost |
| 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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant); 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 diabetesautosomal dominantsubmitted as: Monogenic diabetes
- 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 Ashkenazi Jewish: AF 2.81% (826 of 29,378 alleles), 5.5x the global figure. The global AF describes the general population, not the at-risk group.
35 homozygotes reported in gnomAD v4 (8 Ashkenazi Jewish; 1 Middle Eastern; 9 South Asian; 1 Remaining individuals; 16 European (non-Finnish)). 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. |
|---|---|---|---|---|
| Ashkenazi Jewish | 2.81% | 826 / 29,378 | 8 | ~1 in 18 |
| Middle Eastern | 1.08% | 65 / 6,038 | 1 | ~1 in 46 |
| South Asian | 0.765% | 694 / 90,750 | 9 | ~1 in 65 |
| Remaining individuals | 0.589% | 366 / 62,128 | 1 | ~1 in 85 |
| European (non-Finnish) | 0.503% | 5,911 / 1,174,286 | 16 | ~1 in 99 |
| Finnish | 0.187% | 116 / 62,134 | 0 | ~1 in 270 |
| Admixed American | 0.181% | 108 / 59,828 | 0 | ~1 in 280 |
| African / African American | 0.063% | 47 / 74,904 | 0 | ~1 in 800 |
| East Asian | 0.0045% | 2 / 44,706 | 0 | ~1 in 11180 |
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 818 sits in wolframin's C-terminal lumenal domain. Neighbors: GLN819 (2.4 Å — same Q819 contacted by K705N/E across the fold!), LEU817 (2.5 Å), SER821 (4.4 Å — same S821 contacted by R703C across the fold). The Q819 and S821 contacts are structurally significant — R818 sits in a long-range contact network with the R705-Q819 microregion.
Replacing R818 with cysteine eliminates the positive charge contributing to the Q819 contact and introduces a free thiol into the oxidizing ER lumen. The new C818 could engage in aberrant disulfide chemistry with nearby cysteines (no immediate cysteine partners within 5 Å, but the lumenal domain has multiple cysteines that could be reached).
The ΔΔG of +0.24 is mild stabilising — the fold packs efficiently with the smaller cysteine. AlphaMissense's 0.38 is below threshold (AM under-call). Multi-phenotype clinical evidence (monogenic diabetes + WFS1 spectrum) does not resolve pathogenicity (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: loss of R818 charge from Q819-S821 long-range contact network + free-thiol introduction with aberrant disulfide risk. Therapeutic strategy: site-directed at the Q819 microregion (shared with K705N/E).
Why this matters
Feed this card to Wolfram Intelligence
Download the R818C 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.