R138C
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialArginine → Cysteine at position 138 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.29 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.72. R→C class.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P100 | — | Lost |
| Hydrogen bond | A133 | A133 | Preserved |
| Hydrogen bond | — | E140 | Gained |
| Hydrogen bond | A141 | A141 | Preserved |
| Hydrogen bond | V142 | V142 | Preserved |
| Polar contact | P100 | — | Lost |
| Polar contact | T104 | — | Lost |
| Polar contact | A133 | A133 | Preserved |
| Polar contact | E140 | — | Lost |
| Polar contact | A141 | — | Lost |
| Polar contact | V142 | V142 | Preserved |
| Van der Waals | K101 | — | Lost |
| Van der Waals | A133 | A133 | Preserved |
| Hydrophobic | A133 | — | Lost |
| Hydrophobic | A141 | A141 | 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 at very low frequency in gnomAD.
Structural Context
Position 138 in N-term. Neighbors: ARG139 (2.5 Å — adjacent existing arginine), GLY137 (2.5 Å), ALA133 (3.8 Å — A133T position). The wild-type R138 sits adjacent to R139 — two consecutive arginines in the cytoplasmic domain.
R138C eliminates one of the two adjacent positives and introduces a free thiol. In cytosol, the thiol is less reactive than in ER lumen but can still participate in glutathionylation or regulatory thiol chemistry. AM 0.29 under-call; Wolfram 1 confirms pathogenicity.
Druggability Assessment
Mechanism: charge loss from R138-R139 cluster + thiol introduction. Therapeutic: same N-term microregion (with A133T adjacent).
Why this matters
Feed this card to Wolfram Intelligence
Download the R138C 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.