R457S
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialArginine → Serine at position 457 in connecting loop. ClinVar Conflicting including monogenic diabetes + spastic. AlphaMissense 0.515 (borderline), ΔΔG -0.82.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P453 | P453 | Preserved |
| Hydrogen bond | Y454 | Y454 | Preserved |
| Hydrogen bond | A460 | A460 | Preserved |
| Hydrogen bond | T461 | T461 | Preserved |
| Polar contact | P453 | P453 | Preserved |
| Polar contact | Y454 | Y454 | Preserved |
| Polar contact | — | T455 | Gained |
| Polar contact | A460 | A460 | Preserved |
| Polar contact | T461 | T461 | Preserved |
| Polar contact | — | L514 | Gained |
| Hydrophobic | L514 | — | 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 457 in connecting loop. Neighbors: ALA458 (2.5 Å), ARG456 (2.5 Å — adjacent existing arginine!), TYR454 (3.7 Å), PRO453 (4.1 Å).
Replacing R457 with serine eliminates one of two adjacent arginines (R456 + R457). The local positively-charged surface character is reduced. ΔΔG 0.82 + AM 0.515 borderline + monogenic diabetes confirm severe consequence.
Druggability Assessment
Mechanism: loss of R457 charge from R456-R457 cluster. Therapeutic: site-directed at the loop's charged surface.
Why this matters
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