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
Clinical Evidence
Observed in the general population.
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) confirms pathogenicity.
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
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