P724L
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialProline → Leucine at position 724 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.906, ΔΔG -0.24. Same position as P724S (Atlas card adjacent) — proline-removal pair.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I727 | I727 | Preserved |
| Hydrogen bond | G728 | G728 | Preserved |
| Polar contact | F726 | F726 | Preserved |
| Polar contact | I727 | I727 | Preserved |
| Polar contact | G728 | G728 | Preserved |
| Van der Waals | — | F726 | Gained |
| Hydrophobic | F726 | F726 | 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 724 same neighbors as P724S: LEU723 (2.5 Å — partner of L723P), PHE725 (2.5 Å), PHE726 (4.6 Å), ILE727 (5.0 Å).
P724L is the second substitution at 724 (with P724S). Where P724S added polarity into hydrophobic environment, P724L is conservative hydrophobic-to-hydrophobic. Both lose the backbone kink. Combined with L723P, three Atlas variants converge on the 723-724 Leu-Pro motif.
|ΔΔG| 0.24 + AlphaMissense 0.906 confirm severe consequence.
Druggability Assessment
Mechanism: loss of wild-type Leu-Pro backbone geometry. Therapeutic: same target as L723P, P724S.
Why this matters
Feed this card to Wolfram Intelligence
Download the P724L 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.