R708C
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialArginine → Cysteine at position 708. ClinVar Conflicting (monogenic diabetes, inborn genetic diseases, retinal). AlphaMissense 0.973, ΔΔG -0.36. R→C charge loss + free thiol in ER lumen.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E776 | — | Lost |
| Hydrogen bond | F775 | — | Lost |
| Hydrogen bond | E776 | E776 | Preserved |
| Polar contact | — | T710 | Gained |
| Polar contact | F775 | — | Lost |
| Polar contact | E776 | E776 | Preserved |
| Carbonyl | F775 | — | Lost |
| Van der Waals | F775 | — | Lost |
| Van der Waals | E776 | — | Lost |
| Hydrophobic | T710 | — | Lost |
| Hydrophobic | E776 | — | 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 at very low frequency in gnomAD.
Structural Context
Position 708 sits in the lumenal domain. Neighbors: VAL709 (2.4 Å), VAL707 (2.5 Å — partner of V707F), GLU776 (3.8 Å — likely wild-type salt-bridge partner).
R708C is the second pathogenic substitution at position 708 (with R708L). The mechanism overlaps but differs: R708L removes the charge cleanly with hydrophobic replacement; R708C removes the charge AND introduces a free thiol into the oxidizing ER lumen. The new C708 could engage in aberrant disulfide formation with nearby cysteines, creating misfolding pressure that DynaMut2's |ΔΔG| of 0.36 does not capture.
AlphaMissense 0.973 + monogenic diabetes + retinal phenotype confirm severe functional consequence across tissues.
Druggability Assessment
Mechanism: loss of R708-E776 salt bridge plus free-thiol misfolding pressure. Therapeutic: site-directed at the E776 microregion, with attention to oxidative chemistry risk.
Why this matters
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