D771Y
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAspartate → Tyrosine at position 771. ClinVar Conflicting. AlphaMissense 0.855, ΔΔG +0.18. Third variant at position 771 — same as D771H plus the N714 network position.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | I712 | Gained |
| Hydrogen bond | N714 | — | Lost |
| Hydrogen bond | K768 | K768 | Preserved |
| Hydrogen bond | Y773 | Y773 | Preserved |
| Polar contact | N714 | — | Lost |
| Polar contact | K768 | K768 | Preserved |
| Polar contact | Y773 | Y773 | Preserved |
| Aromatic / π | — | Y773 | Gained |
| Van der Waals | — | N714 | Gained |
| Van der Waals | K768 | K768 | Preserved |
| Van der Waals | Y773 | — | Lost |
| Hydrophobic | I712 | I712 | Preserved |
| Hydrophobic | — | N714 | Gained |
| Hydrophobic | — | K768 | Gained |
| Hydrophobic | Y773 | Y773 | 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 771 same neighbors as D771H: ARG772 (2.4 Å — salt-bridge partner), PHE770 (2.5 Å), LYS768 (3.8 Å), ASP713 (3.8 Å — same D713 in the N714 polar network).
D771Y is the second pathogenic substitution at position 771 (with D771H). Where D771H reversed charge and added aromatic, D771Y eliminates charge entirely and adds aromatic volume. The R772 salt-bridge is broken; the F770 aromatic now has a tyrosine neighbor creating a tandem aromatic.
ΔΔG essentially neutral; AM 0.855 confirms severe consequence.
Druggability Assessment
Mechanism: loss of D771-R772 salt bridge + tandem aromatic formation. Therapeutic: same D771 microregion as D771H, N714T/S/K.
Why this matters
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