P607R
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialProline → Arginine at position 607 inside TM9. ClinVar Conflicting. AlphaMissense 0.922, ΔΔG +0.03 (neutral). pLDDT 66 borderline. Proline-removal in TM9 with charge introduction.
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 |
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 sits near the end of TM9. Neighbors: LEU608 (2.5 Å), VAL606 (2.5 Å), LEU610 (4.1 Å), SER605 (4.5 Å).
The wild-type proline likely defines a helix-end geometry. Replacing it with arginine removes the kink and introduces charge near the membrane-water interface. The near-zero ΔΔG reflects fold accommodation through the arginine extending toward solvent.
AlphaMissense 0.922 confirms severe consequence. P607L (Atlas card next) is the same position with leucine — both pathogenic.
Druggability Assessment
Mechanism: loss of TM9 helix-end kink plus charge introduction. Therapeutic: site-directed at the TM9 C-terminal region.
Why this matters
Feed this card to Wolfram Intelligence
Download the P607R 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.