A844V
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAlanine → Valine at position 844 in lumenal C-terminal region. ClinVar Conflicting including spastic ataxia. AlphaMissense 0.782, ΔΔG +0.09 (near-neutral).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | F825 | — | Lost |
| Hydrogen bond | S826 | S826 | Preserved |
| Hydrogen bond | V861 | V861 | Preserved |
| Polar contact | F825 | F825 | Preserved |
| Polar contact | S826 | S826 | Preserved |
| Polar contact | L842 | L842 | Preserved |
| Polar contact | V861 | V861 | Preserved |
| Carbonyl | F825 | — | Lost |
| Van der Waals | F825 | — | Lost |
| Van der Waals | S826 | S826 | Preserved |
| Van der Waals | — | K862 | Gained |
| Hydrophobic | K862 | K862 | 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 844 sits in the lumenal C-terminus. Neighbors: ILE845 (2.4 Å), LYS843 (2.4 Å — partner of K843 cluster from L842F), VAL861 (3.2 Å — long-range; near K862N), SER826 (3.7 Å).
The wild-type alanine provides minimal volume. Replacing it with valine introduces branched aliphatic into a pocket sized for alanine. The K843-A844-V861 microregion is perturbed. AM 0.782 + spastic ataxia confirm severe consequence.
Druggability Assessment
Mechanism: volume mismatch in the K843-V861 long-range microregion. Therapeutic: site-directed at the C-terminal cluster (with L842F, K862N targets).
Why this matters
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