P607L
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialProline → Leucine at position 607 inside TM9. ClinVar Conflicting including monogenic diabetes, T2D, DFNA6. AlphaMissense 0.416 (below threshold), ΔΔG -0.27. Same position as P607R — proline-removal pair.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | C604 | — | Lost |
| Hydrogen bond | L610 | L610 | Preserved |
| Hydrogen bond | R611 | R611 | Preserved |
| Polar contact | V603 | — | Lost |
| Polar contact | C604 | — | Lost |
| Polar contact | L610 | L610 | Preserved |
| Polar contact | R611 | R611 | Preserved |
| Van der Waals | R611 | — | Lost |
| Hydrophobic | — | L610 | 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 607 same neighbors as P607R: LEU608 (2.5 Å), VAL606 (2.5 Å), LEU610 (4.1 Å), SER605 (4.5 Å).
P607L is the second pathogenic substitution at 607 (with P607R). Both remove the wild-type proline kink at TM9's end. P607L is the conservative hydrophobic substitution; P607R adds charge.
AM 0.416 below threshold but multi-phenotype confirms pathogenicity.
Druggability Assessment
Mechanism: same TM9 kink-removal as P607R. Therapeutic: TM9 site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the P607L 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.