ATP12A

Chr 13

ATPase H+/K+ transporting non-gastric alpha2 subunit

Also known as: ATP1AL1, H-K-ATPase, HK

NCBI Gene: 479 ENSG00000075673 UniProt: P54707

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.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This gene encodes a catalytic subunit of the ouabain-sensitive H+/K+ -ATPase that catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. It is also responsible for potassium absorption in various tissues. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.60

OE 0.60 (0.44–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.90 (0.84–0.97)

547 obs / 604.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.44–0.81)

0≤0.351.4

Missense OE?0.90 (0.84–0.97)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 29 / 48.5Missense obs/exp: 547 / 604.7Syn Z: 0.35

Background carrier burden — how many people carry a rare variant somewhere in ATP12A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 47

1,290 rare PASS variants

Rare truncating (LoF)

1 in 150

203 rare PASS variants

Rare synonymous (reference)

1 in 85

532 rare PASS variants

Rare missense and truncating variants are carried at similar rates in ATP12A; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 57	1 in 300
South Asian	~43k	1 in 43	1 in 160
Remaining (unassigned)	~30k	1 in 36	1 in 210
European (Finnish)	~27k	1 in 92	1 in 2,400
Admixed American	~22k	1 in 49	1 in 320
African / African American	~21k	1 in 34	1 in 300
East Asian	~20k	1 in 54	1 in 340
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 48	1 in 220

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 23 of 23 coding exons well covered in gnomAD exomes. Genomes: 22 of 23 (exon 6 below).? see exons ↓