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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Ataxia / spastic ataxia (inheritance not specified).
- Ataxia / spastic ataxiainheritance not specifiedsubmitted as: Spastic ataxia
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0075% (88 of 1,179,828 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.0075% | 88 / 1,179,828 | 0 | ~1 in 6700 |
| African / African American | 0.0040% | 3 / 74,948 | 0 | ~1 in 12490 |
| Remaining individuals | 0.0032% | 2 / 62,444 | 0 | ~1 in 15610 |
| Admixed American · under-sampled | 0.0017% | 1 / 60,002 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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
Feed this card to Wolfram Intelligence
Download the A844V 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.