R653C
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArginine → Cysteine at position 653 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.476 (below threshold), ΔΔG +0.22. pLDDT 61 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | F649 | F649 | Preserved |
| Hydrogen bond | Y650 | Y650 | Preserved |
| Hydrogen bond | G656 | G656 | Preserved |
| Polar contact | F649 | F649 | Preserved |
| Polar contact | Y650 | Y650 | Preserved |
| Polar contact | V651 | V651 | Preserved |
| Polar contact | G656 | G656 | Preserved |
| Van der Waals | — | Y650 | Gained |
| Van der Waals | V651 | V651 | Preserved |
| Van der Waals | E655 | E655 | Preserved |
| Hydrophobic | F649 | — | 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
Clinical Evidence
Observed in the general population.
Structural Context
Position 653 at the lumenal domain start. Neighbors: SER654 (2.5 Å), TYR652 (2.5 Å), TYR650 (3.6 Å — Y650H/Y650D/Y650C region!), PHE649 (3.8 Å — Y650 cluster).
R653C sits adjacent to the Y650 aromatic cluster (multiple Atlas variants at Y650). The introduced thiol could engage in aberrant disulfide chemistry. AM 0.476 below threshold but multi-phenotype + ClinVar Pathogenic raise concern.
Druggability Assessment
Mechanism: charge loss + thiol near Y650 cluster. Therapeutic: same Y650 microregion. Wet-lab validation recommended.
Why this matters
Feed this card to Wolfram Intelligence
Download the R653C 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.