Y650D
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialTyrosine → Aspartate at position 650 inside TM10. ClinVar Likely pathogenic. AlphaMissense 0.829, DynaMut2 ΔΔG +0.38 STABILISING. pLDDT 69 borderline. Same position as Y650H (Atlas card adjacent) but with charge introduction.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I338 | — | Lost |
| Hydrogen bond | F646 | F646 | Preserved |
| Hydrogen bond | C647 | C647 | Preserved |
| Hydrogen bond | R653 | — | Lost |
| Hydrogen bond | S654 | S654 | Preserved |
| Polar contact | F646 | F646 | Preserved |
| Polar contact | C647 | C647 | Preserved |
| Polar contact | W648 | W648 | Preserved |
| Polar contact | Y652 | — | Lost |
| Polar contact | R653 | R653 | Preserved |
| Polar contact | S654 | S654 | Preserved |
| Van der Waals | W648 | W648 | 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 650 sits at the end of TM10, in the same aromatic-rich pocket discussed in the Y650H Atlas card: PHE649 (2.5 Å), VAL651 (2.5 Å), CYS647 (3.7 Å), PHE646 (3.7 Å), TRP648 (4.4 Å).
Replacing tyrosine with aspartate is more disruptive than Y650H. Y650H preserved aromatic character (histidine imidazole). Y650D eliminates the aromatic ring entirely and introduces a small carboxylate where the wild-type phenol provided bulky aromatic packing. The aromatic cluster (F646, F649, W648) loses its tyrosine partner; the new carboxylate is also unfavorable in the bilayer-embedded environment.
The DynaMut2 ΔΔG of +0.38 (stabilising) is surprising — possibly because the aspartate can extend toward the lumenal face of TM10 where its charge is more compatible. AlphaMissense's 0.829 + ClinVar Pathogenic confirm severe functional consequence despite the stabilization.
Druggability Assessment
Mechanism is loss of Y650 aromatic packing with the TM10 C-terminal aromatic cluster (F646, F649, W648). Therapeutic strategy: same microregion as Y650H.
Why this matters
Feed this card to Wolfram Intelligence
Download the Y650D 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.