ATP12A
Chr 13ATPase H+/K+ transporting non-gastric alpha2 subunit
Also known as: ATP1AL1, H-K-ATPase, HK
ATP12A encodes the catalytic subunit of a H+/K+ ATPase pump that transports potassium ions in exchange for sodium and hydrogen ions across epithelial cell membranes, maintaining electrolyte homeostasis in kidney, colon, and airways. Mutations cause autosomal recessive neurogenic arthrogryposis multiplex congenita, a condition characterized by joint contractures and neurological abnormalities present from birth. This gene shows very low constraint against loss-of-function variants, consistent with recessive inheritance requiring biallelic mutations to cause disease.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
218 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 33 | 0 | 33 |
Likely Pathogenic | 0 | 0 | 2 | 0 | 2 |
VUS | 1 | 153 | 13 | 0 | 167 |
Likely Benign | 0 | 2 | 1 | 5 | 8 |
Benign | 1 | 0 | 0 | 0 | 1 |
| Total | 2 | 155 | 49 | 5 | 211 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
ATP12A · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
A Study to Evaluate the Impact of Lactobacillus Rhamnosus GG on Proton Pump Inhibitor-Induced Gut Dysbiosis
RECRUITINGClinical Efficacy Evaluation of Chaizhi Hewei Decoction in the Treatment of Non-Erosive Reflux Disease With Liver-Stomach Disharmony Syndrome
NOT YET RECRUITINGLuminal Fructose Kinetics (MARTINI Study)
RECRUITINGIntestinal Microbiota After PPI Treatment
NOT YET RECRUITINGOptimization of Keverprazan-amoxicillin Dual Therapy for Eradicating Helicobacter Pylori Infection
RECRUITINGEvidence Based Probiotic Therapy of Proton Pump Inhibitor Induced Dysbiosis
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools