S469L
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialSerine → Leucine at position 469 inside TM5. ClinVar Conflicting. AlphaMissense 0.18 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.14.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A465 | A465 | Preserved |
| Hydrogen bond | G466 | G466 | Preserved |
| Hydrogen bond | P472 | P472 | Preserved |
| Polar contact | A465 | A465 | Preserved |
| Polar contact | G466 | G466 | Preserved |
| Polar contact | P472 | P472 | Preserved |
| Van der Waals | — | L467 | Gained |
| Van der Waals | — | L471 | Gained |
| Van der Waals | — | F884 | Gained |
| Hydrophobic | — | P504 | Gained |
| Hydrophobic | — | F884 | Gained |
| Hydrophobic | — | P885 | Gained |
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 469 in TM5 — first TM5 variant at v3 depth. Neighbors: LEU468 (2.5 Å), LEU470 (2.5 Å), GLY466 (3.8 Å). Hydrophobic TM environment.
S469L removes hydroxyl from TM5 (favorable energetically), but the wild-type serine's H-bond capacity supported functional geometry. AM 0.18 under-call; Conflicting evidence.
Druggability Assessment
Mechanism: lost serine H-bonding in TM5. Therapeutic: TM5 site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the S469L 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.