ATP12A

Summary

ATP12A (ATPase H+/K+ transporting non-gastric alpha2 subunit, HGNC:13816) is a protein-coding gene on chromosome 13q12.12, encoding Potassium-transporting ATPase alpha chain 2 (P54707). The catalytic subunit of a H(+)/K(+) ATPase and/or Na(+)/K(+) ATPase pump which transports K(+) ions in exchange for Na(+) and/or H(+) ions across the apical membrane of epithelial cells.

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.

Source: NCBI Gene 479 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 180 total — 2 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001676

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13816
Approved symbol	ATP12A
Name	ATPase H+/K+ transporting non-gastric alpha2 subunit
Location	13q12.12
Locus type	gene with protein product
Status	Approved
Aliases	HK, H-K-ATPase
Ensembl gene	ENSG00000075673
Ensembl biotype	protein_coding
OMIM	182360
Entrez	479

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000218548, ENST00000381946, ENST00000911814

RefSeq mRNA: 2 — MANE Select: NM_001676 NM_001185085, NM_001676

CCDS: CCDS31948, CCDS53858

Canonical transcript exons

ENST00000381946 — 23 exons

Exon	Start	End
ENSE00000938438	24685314	24685373
ENSE00000938439	24688319	24688522
ENSE00000938440	24689262	24689375
ENSE00000938441	24690338	24690472
ENSE00000938442	24690604	24690721
ENSE00000938443	24690982	24691250
ENSE00000938444	24692429	24692627
ENSE00000938445	24692787	24692896
ENSE00000938446	24694444	24694578
ENSE00000938447	24698658	24698850
ENSE00000938448	24700747	24700922
ENSE00000938449	24701935	24702071
ENSE00000938450	24706313	24706463
ENSE00000938452	24707279	24707433
ENSE00000938453	24709364	24709487
ENSE00000938454	24709683	24709828
ENSE00001144997	24711318	24711409
ENSE00001145002	24710792	24710893
ENSE00001145006	24710460	24710593
ENSE00001161894	24681562	24681720
ENSE00001652972	24707023	24707191
ENSE00001897561	24711494	24712472
ENSE00001952034	24680408	24680752

Expression profiles

Bgee: expression breadth broad, 92 present calls, max score 89.59.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.3717 / max 550.4377, expressed in 181 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134444	0.8248	126
134445	0.5469	101

Top tissues by expression

269 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trachea	UBERON:0003126	89.59	gold quality
nasal cavity epithelium	UBERON:0005384	87.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.25	gold quality
epithelium of bronchus	UBERON:0002031	85.15	gold quality
epithelium of nasopharynx	UBERON:0001951	85.13	gold quality
bronchus	UBERON:0002185	84.91	gold quality
bronchial epithelial cell	CL:0002328	83.14	gold quality
nasal cavity mucosa	UBERON:0001826	78.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.88	gold quality
lower esophagus mucosa	UBERON:0035834	71.95	gold quality
esophagus squamous epithelium	UBERON:0006920	70.61	gold quality
mammalian vulva	UBERON:0000997	68.29	gold quality
mucosa of paranasal sinus	UBERON:0005030	68.20	silver quality
epithelium of esophagus	UBERON:0001976	67.92	gold quality
oral cavity	UBERON:0000167	66.92	gold quality
upper leg skin	UBERON:0004262	66.36	gold quality
palpebral conjunctiva	UBERON:0001812	65.59	gold quality
upper arm skin	UBERON:0004263	64.65	silver quality
squamous epithelium	UBERON:0006914	64.24	silver quality
hair follicle	UBERON:0002073	64.06	gold quality
skin of abdomen	UBERON:0001416	63.57	gold quality
amniotic fluid	UBERON:0000173	62.36	gold quality
pancreatic ductal cell	CL:0002079	61.14	silver quality
adult mammalian kidney	UBERON:0000082	60.96	gold quality
esophagus mucosa	UBERON:0002469	60.60	gold quality
penis	UBERON:0000989	59.89	silver quality
secondary oocyte	CL:0000655	59.88	gold quality
cranial nerve II	UBERON:0000941	58.59	silver quality
zone of skin	UBERON:0000014	58.17	gold quality
tonsil	UBERON:0002372	58.11	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	51.66
E-ANND-3	yes	5.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB1, SP1, SP3

miRNA regulators (miRDB)

47 targeting ATP12A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-885-5P	99.59	68.59	879

Literature-anchored findings (GeneRIF, showing 12)

• The presence of nongastric H-K-ATPase in rodent prostate apical membranes may indicate its involvement in potassium concentration regulation in secretions of these glands. (PMID:11880279)
• Stimulation of protein kinase C pathway mediates endocytosis of human nongastric H+-K+-ATPase, ATP1AL1. (PMID:12110518)
• Expressed in distal part of human colon and rectum, but also in proximal part of colon. Overexpressed in human colorectal adenocarcinomas adenocarcinomas. Astonishing levels of mRNA overexpression in carcinoma. (PMID:12230809)
• Carboxy-terminus of HKalpha(2) facilitates proper folding of tHKalpha(2)/beta(1) complex allowing translocation of heterodimer to plasma membrane where potassium uptake occurs. Otherwise, alpha/beta complex is destined for degradation. (PMID:15086469)
• non-gastric H(+)/K(+)ATPase is present in the microvillous plasma membrane of the transporting epithelia of the human placenta (PMID:15135233)
• Inhibition of the ATP1AL1 isoenzyme of sodium potassium exchanging ATPase by 8-coumestrol is reported. (PMID:19487957)
• Use of fold recognition methods enables a prediction that the C-terminal domain of the beta subunits of Na,K-ATPase and H,K-ATPase has an immunoglobulin-like fold, which resembles cell adhesion molecules. (PMID:19694409)
• No significantly different expression levels could be detected in the various disease states compared to normal tissue. (PMID:22179016)
• Genetic association studies show that carriers of ATP12A rs10507337 C allele or CCTTC haplotype had better pattern of myocardial relaxation as compared to non-carriers. (PMID:25366262)
• expressing human ATP12A in cystic fibrosis mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. (PMID:26823428)
• ATP12A knockdown or inhibition prevented the IL-13 dependent increase in airway surface liquid (ASL) viscosity but did not alter the ASL pH (PMID:29391451)
• Study in fresh bronchial samples and in cultured epithelial cells found that ATP12A expressed almost exclusively at the apical side of non-ciliated cells of airway epithelium and in submucosal glands, with much higher expression in cystic fibrosis samples. ATP12A upregulation is associated with depletion of K+ in airway surface liquid, an effect that may have an important role in the barrier function of airway epithelium. (PMID:30333310)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
mus_musculus	Atp12a	ENSMUSG00000022229
rattus_norvegicus	Atp12a	ENSRNOG00000020685
drosophila_melanogaster	anne	FBGN0052000
drosophila_melanogaster	SPoCk	FBGN0052451
drosophila_melanogaster	CG45062	FBGN0266432
drosophila_melanogaster	CG45063	FBGN0266433
caenorhabditis_elegans		WBGENE00000834
caenorhabditis_elegans	pmr-1	WBGENE00004063
caenorhabditis_elegans		WBGENE00012341
caenorhabditis_elegans		WBGENE00015338
caenorhabditis_elegans		WBGENE00015660

Paralogs (21): ATP2C1 (ENSG00000017260), ATP1A2 (ENSG00000018625), ATP2B4 (ENSG00000058668), ATP2C2 (ENSG00000064270), ATP2B3 (ENSG00000067842), ATP2B1 (ENSG00000070961), ATP2A3 (ENSG00000074370), ATP1A3 (ENSG00000105409), ATP4A (ENSG00000105675), ATP13A1 (ENSG00000105726), ATP7B (ENSG00000123191), ATP13A4 (ENSG00000127249), ATP1A4 (ENSG00000132681), ATP13A3 (ENSG00000133657), ATP2B2 (ENSG00000157087), ATP13A2 (ENSG00000159363), ATP1A1 (ENSG00000163399), ATP7A (ENSG00000165240), ATP2A2 (ENSG00000174437), ATP13A5 (ENSG00000187527), ATP2A1 (ENSG00000196296)

Protein

Protein identifiers

Potassium-transporting ATPase alpha chain 2 — P54707 (reviewed: P54707)

Alternative names: HK alpha 2, Non-gastric H(+)/K(+) ATPase subunit alpha, Non-gastric Na(+)/K(+) ATPase subunit alpha, Proton pump, Sodium pump

All UniProt accessions (1): P54707

UniProt curated annotations — full annotation on UniProt →

Function. The catalytic subunit of a H(+)/K(+) ATPase and/or Na(+)/K(+) ATPase pump which transports K(+) ions in exchange for Na(+) and/or H(+) ions across the apical membrane of epithelial cells. Uses ATP as an energy source to pump K(+) ions into the cell while transporting Na(+) and/or H(+) ions to the extracellular compartment. Involved in the maintenance of electrolyte homeostasis through K(+) ion absorption in kidney and colon. In the airway epithelium, may play a primary role in mucus acidification regulating its viscosity and clearance.

Subunit / interactions. The ATPase pump is composed of a catalytic alpha subunit and an auxiliary non-catalytic beta subunit. The alpha subunit pairs with the beta subunit of gastric H(+)/K(+) ATPase ATP4B or the beta subunit of Na(+)/K(+) ATPases ATP1B1 and ATP1B3; this interaction is required for the formation of a functionally active pump and its targeting at the plasma membrane.

Subcellular location. Apical cell membrane.

Tissue specificity. Expressed in airway epithelial cells (at protein level). Found in skin and kidney. Detected in prostate basal cells (at protein level). Expression is increased in benign prostate hyperplasia and tumor tissues (at protein level).

Activity regulation. The ATPase activity is regulated by monovalent cations and pH. Up-regulated by K(+) ions in a dose-dependent way. Down-regulated by Na(+) ions. Inhibited by Na(+)/K(+)-ATPase inhibitor ouabain and H(+)/K(+)-ATPase inhibitor SCH-28080 with an intermediate sensitivity to completely resistant Na(+)/K(+)-ATPases and highly sensitive H(+)/K(+)-ATPases.

Induction. Up-regulated by inflammatory cytokine IL13.

Similarity. Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIC subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P54707-1	1	yes
P54707-2	2

RefSeq proteins (2): NP_001172014, NP_001667* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001757	P_typ_ATPase	Family
IPR004014	ATPase_P-typ_cation-transptr_N	Domain
IPR005775	P-type_ATPase_IIC	Family
IPR006068	ATPase_P-typ_cation-transptr_C	Domain
IPR008250	ATPase_P-typ_transduc_dom_A_sf	Homologous_superfamily
IPR018303	ATPase_P-typ_P_site	PTM
IPR023214	HAD_sf	Homologous_superfamily
IPR023298	ATPase_P-typ_TM_dom_sf	Homologous_superfamily
IPR023299	ATPase_P-typ_cyto_dom_N	Homologous_superfamily
IPR036412	HAD-like_sf	Homologous_superfamily
IPR044492	P_typ_ATPase_HD_dom	Domain
IPR050510	Cation_transp_ATPase_P-type	Family
IPR059000	ATPase_P-type_domA	Domain

Pfam: PF00122, PF00689, PF00690, PF08282, PF13246

Enzyme classification (BRENDA):

• EC 7.2.2.19 — H+/K+-exchanging ATPase (BRENDA: 23 organisms, 73 substrates, 240 inhibitors, 15 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0245–1.2	5
K+	0.3–20	5
K+[SIDE 2]	0.4–5.5	3

Catalyzed reactions (Rhea), 2 shown:

• K(+)(out) + Na(+)(in) + ATP + H2O = K(+)(in) + Na(+)(out) + ADP + phosphate + H(+) (RHEA:18353)
• K(+)(out) + ATP + H2O + H(+)(in) = K(+)(in) + ADP + phosphate + 2 H(+)(out) (RHEA:22044)

UniProt features (36 total): topological domain 11, transmembrane region 10, sequence conflict 7, binding site 2, chain 1, active site 1, modified residue 1, splice variant 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54707-F1	85.32	0.47

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 391 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (2): 732; 736

Post-translational modifications (1): 958

Mutagenesis-validated functional residues (1):

Position	Phenotype
329	abolishes targeting to the apical plasma membrane.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 142 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_TRANSMEMBRANE_ELECTROCHEMICAL_GRADIENT, WWTAAGGC_UNKNOWN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POTASSIUM_ION_HOMEOSTASIS, ONDER_CDH1_TARGETS_3_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_INTRACELLULAR_POTASSIUM_ION_HOMEOSTASIS, GOBP_INTRACELLULAR_SODIUM_ION_HOMEOSTASIS, GOBP_SODIUM_ION_HOMEOSTASIS, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOBP_REGULATION_OF_PH, GOCC_APICAL_PLASMA_MEMBRANE

GO Biological Process (11): intracellular sodium ion homeostasis (GO:0006883), regulation of pH (GO:0006885), intracellular potassium ion homeostasis (GO:0030007), sodium ion export across plasma membrane (GO:0036376), proton transmembrane transport (GO:1902600), potassium ion import across plasma membrane (GO:1990573), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), establishment or maintenance of transmembrane electrochemical gradient (GO:0010248), potassium ion homeostasis (GO:0055075)

GO Molecular Function (8): P-type sodium:potassium-exchanging transporter activity (GO:0005391), ATP binding (GO:0005524), P-type potassium:proton transporter activity (GO:0008900), ATP hydrolysis activity (GO:0016887), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), transporter activity (GO:0005215), P-type potassium transmembrane transporter activity (GO:0008556)

GO Cellular Component (9): cytosol (GO:0005829), plasma membrane (GO:0005886), potassium:proton exchanging ATPase complex (GO:0005889), actin cytoskeleton (GO:0015629), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), membrane (GO:0016020), cation-transporting ATPase complex (GO:0090533), plasma membrane protein complex (GO:0098797)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular monoatomic cation homeostasis	2
monoatomic cation homeostasis	2
metal ion transport	2
P-type potassium transmembrane transporter activity	2
cellular anatomical structure	2
plasma membrane region	2
sodium ion homeostasis	1
biological regulation	1
potassium ion homeostasis	1
sodium ion transmembrane transport	1
export across plasma membrane	1
monoatomic cation transmembrane transport	1
potassium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
transport	1
monoatomic ion transmembrane transport	1
inorganic ion homeostasis	1
P-type sodium transporter activity	1
establishment or maintenance of transmembrane electrochemical gradient	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
P-type proton-exporting transporter activity	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
potassium ion transmembrane transporter activity	1
P-type ion transporter activity	1
ATPase-coupled monoatomic cation transmembrane transporter activity	1
cytoplasm	1
membrane	1
cell periphery	1
cation-transporting ATPase complex	1
plasma membrane protein complex	1
cytoskeleton	1
basal plasma membrane	1
apical part of cell	1
ATPase dependent transmembrane transport complex	1

Protein interactions and networks

STRING

3310 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP12A	CYP2C19	P33259	944
ATP12A	GAST	P01350	934
ATP12A	TCIRG1	Q13488	923
ATP12A	ATP6V1B1	P15313	917
ATP12A	ATP6V0A4	Q9HBG4	902
ATP12A	ATP6V0A1	Q93050	885
ATP12A	HRH2	P25021	880
ATP12A	ATP6V0C	P27449	837
ATP12A	CLCN7	P51798	826
ATP12A	ATP6V0A2	Q9Y487	825
ATP12A	ATP6V1D	Q9Y5K8	818
ATP12A	ATP4B	P51164	808
ATP12A	CA2	P00918	792
ATP12A	ALB	P02768	773
ATP12A	ACE	P12821	771

IntAct

176 interactions, top by confidence:

A	B	Type	Score
ATP1B1	ATP1A1	psi-mi:“MI:0914”(association)	0.910
TNFRSF9	TNFSF9	psi-mi:“MI:0914”(association)	0.820
HS2ST1	SLC7A1	psi-mi:“MI:0914”(association)	0.730
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
RETREG3	PLSCR1	psi-mi:“MI:0914”(association)	0.640
TMED2	ATP9A	psi-mi:“MI:0914”(association)	0.640
AUP1	APOB	psi-mi:“MI:0914”(association)	0.610
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
SLC2A5	RBFOX3	psi-mi:“MI:0914”(association)	0.530
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
TRABD	FCN1	psi-mi:“MI:0914”(association)	0.530
ITM2A	NDUFB5	psi-mi:“MI:0914”(association)	0.530
WBP1	EXTL3	psi-mi:“MI:0914”(association)	0.530
HSD17B6	NME2P1	psi-mi:“MI:0914”(association)	0.530
PRG3	ZNF324	psi-mi:“MI:0914”(association)	0.530
HLA-B	LTN1	psi-mi:“MI:0914”(association)	0.530
SLC22A15	ZFPL1	psi-mi:“MI:0914”(association)	0.530
SRPRB	CTDNEP1	psi-mi:“MI:0914”(association)	0.530
IRGC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
DLK1	SCAMP3	psi-mi:“MI:0914”(association)	0.530
ATP1A3	AGPAT2	psi-mi:“MI:0914”(association)	0.530
P2RY14	ATP12A	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (257): ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP12A (Affinity Capture-MS)

ESM2 similar proteins: A2VDL6, D2WKD8, P04074, P05023, P05024, P05025, P06685, P06686, P06687, P07038, P09572, P09626, P13607, P13637, P17326, P18907, P19156, P20648, P24797, P24798, P25489, P27112, P28774, P30714, P35317, P50993, P50996, P50997, P54707, P54708, P58312, Q08DA1, Q13733, Q5RCD8, Q5RDR3, Q64392, Q64436, Q64541, Q6PIC6, Q6PIE5

Diamond homologs: A0A143ZZK9, A2VDL6, A7L9Z8, B9QMJ0, D2WKD8, O08462, O22218, O34431, O59868, O64806, O75185, O77696, O81108, P04074, P05023, P05024, P05025, P06685, P06686, P06687, P09572, P09626, P0ABB8, P0ABB9, P13586, P13607, P13637, P17326, P18398, P18596, P18907, P19156, P20648, P24797, P24798, P25489, P27112, P28774, P30714, P35317

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 260 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ion transport by P-type ATPases	6	7.4×	1e-02
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	13	6.7×	1e-05
Peptide ligand-binding receptors	14	6.1×	1e-05
G alpha (q) signalling events	16	5.4×	1e-05
Class A/1 (Rhodopsin-like receptors)	12	5.3×	4e-04
GPCR ligand binding	11	4.2×	6e-03
G alpha (i) signalling events	14	3.2×	8e-03
Neutrophil degranulation	21	2.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
sodium ion export across plasma membrane	5	22.4×	5e-04
intracellular sodium ion homeostasis	5	16.3×	2e-03
cellular defense response	7	9.5×	2e-03
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	6	8.6×	8e-03
phospholipase C-activating G protein-coupled receptor signaling pathway	13	7.3×	3e-05
positive regulation of cytosolic calcium ion concentration	13	6.5×	5e-05
chemotaxis	11	6.4×	5e-04
G protein-coupled receptor signaling pathway	24	3.7×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

180 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	162
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
155130	GRCh38/hg38 13q12.11-12.13(chr13:19671934-24985872)x1	Pathogenic
564075	GRCh37/hg19 13q12.11-12.13(chr13:20008480-25534121)x1	Pathogenic

SpliceAI

3124 predictions. Top by Δscore:

Variant	Effect	Δscore
13:24685303:A:AG	acceptor_gain	1.0000
13:24685303:AT:A	acceptor_gain	1.0000
13:24685303:ATG:A	acceptor_gain	1.0000
13:24685304:T:G	acceptor_gain	1.0000
13:24685304:T:TA	acceptor_gain	1.0000
13:24688317:AG:A	acceptor_gain	1.0000
13:24688318:GG:G	acceptor_gain	1.0000
13:24689257:CCCA:C	acceptor_loss	1.0000
13:24689258:CCA:C	acceptor_loss	1.0000
13:24689259:CAGGT:C	acceptor_loss	1.0000
13:24689261:G:GA	acceptor_loss	1.0000
13:24689372:TCAG:T	donor_loss	1.0000
13:24689376:G:GC	donor_loss	1.0000
13:24689377:T:G	donor_loss	1.0000
13:24690333:T:A	acceptor_gain	1.0000
13:24690336:A:AG	acceptor_gain	1.0000
13:24690337:G:GT	acceptor_gain	1.0000
13:24690337:GC:G	acceptor_gain	1.0000
13:24690337:GCA:G	acceptor_gain	1.0000
13:24690337:GCAA:G	acceptor_gain	1.0000
13:24690414:TCA:T	donor_gain	1.0000
13:24690420:G:GT	donor_gain	1.0000
13:24690471:GG:G	donor_gain	1.0000
13:24690471:GGGT:G	donor_loss	1.0000
13:24690472:GG:G	donor_gain	1.0000
13:24690473:G:GG	donor_gain	1.0000
13:24690473:GTA:G	donor_loss	1.0000
13:24690474:T:G	donor_loss	1.0000
13:24690598:TTCTA:T	acceptor_loss	1.0000
13:24690599:TCTA:T	acceptor_loss	1.0000

AlphaMissense

6863 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:24692531:G:C	D391H	1.000
13:24692532:A:C	D391A	1.000
13:24692547:T:C	L396P	1.000
13:24701969:C:A	A639D	1.000
13:24701981:C:A	A643D	1.000
13:24707044:G:T	G731W	1.000
13:24707060:A:C	D736A	1.000
13:24692527:C:G	C389W	0.999
13:24692532:A:G	D391G	0.999
13:24692532:A:T	D391V	0.999
13:24692533:C:A	D391E	0.999
13:24692533:C:G	D391E	0.999
13:24692534:A:C	K392Q	0.999
13:24692534:A:G	K392E	0.999
13:24692536:G:C	K392N	0.999
13:24692536:G:T	K392N	0.999
13:24692540:G:T	G394W	0.999
13:24692541:G:A	G394E	0.999
13:24692547:T:A	L396Q	0.999
13:24700864:A:G	D608G	0.999
13:24700894:T:A	V618D	0.999
13:24701953:G:C	D634H	0.999
13:24701954:A:C	D634A	0.999
13:24701954:A:G	D634G	0.999
13:24701954:A:T	D634V	0.999
13:24701968:G:C	A639P	0.999
13:24701980:G:C	A643P	0.999
13:24706411:C:A	A706D	0.999
13:24707036:C:A	A728D	0.999
13:24707044:G:A	G731R	0.999

dbSNP variants (sampled 300 via entrez): RS1000101357 (13:24691098 T>C), RS1000246867 (13:24678590 C>T), RS1000275138 (13:24707831 A>G), RS1000534004 (13:24686851 G>A), RS1000695486 (13:24692188 C>T), RS1000711303 (13:24703658 G>A,C), RS1000810752 (13:24697735 G>T), RS1000888674 (13:24712932 C>T), RS1000972094 (13:24697560 A>G), RS1001028095 (13:24685481 A>AG), RS1001057825 (13:24680275 C>A,G,T), RS1001064697 (13:24703097 C>T), RS1001209486 (13:24685682 C>T), RS1001314861 (13:24691680 C>T), RS1001315609 (13:24691957 G>A,T)

Disease associations

OMIM: gene MIM:182360 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_146	Obesity-related traits	6.000000e-07
GCST006627_4	Diastolic blood pressure	5.000000e-11
GCST007367_6	Meconium ileus in cystic fibrosis	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004908	testosterone measurement
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2933 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 89 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2093999	ISTAROXIME	2	89

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — H⁺/K⁺-ATPases

ChEMBL bioactivities

12 potent at pChembl≥5 of 15 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.52	IC50	30	nM	CHEMBL2068911
7.22	IC50	60	nM	CHEMBL2068890
7.10	IC50	80	nM	DIGITOXIGENIN
7.00	IC50	100	nM	CHEMBL323301
6.92	IC50	120	nM	CHEMBL104027
6.89	IC50	130	nM	CHEMBL318786
6.70	IC50	200	nM	ISTAROXIME
6.70	IC50	200	nM	CHEMBL319670
6.60	IC50	250	nM	CHEMBL321090
6.46	IC50	350	nM	CHEMBL2068917
5.23	IC50	5890	nM	CHEMBL2068987
5.22	IC50	6000	nM	CHEMBL3137924

PubChem BioAssay actives

12 with measured affinity, of 80 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-(dimethylamino)ethyl (E)-3-[(3S,5R,8R,9S,10S,13R,14S,17R)-3,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]prop-2-enoate	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.0300	uM
(E)-3-[(3S,5R,8R,9S,10S,13R,14S,17R)-3,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]prop-2-enal	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.0600	uM
3-[(3S,5R,8R,9S,10S,13R,14S,17R)-3,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2H-furan-5-one	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.0800	uM
2-(dimethylamino)ethyl (2E)-2-[(1R,4bR,7S,8aR)-7-hydroxy-1,4b,8,8-tetramethyl-10-oxo-1,3,4,4a,5,6,7,8a,9,10a-decahydrophenanthren-2-ylidene]acetate	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.1000	uM
2-(dimethylamino)ethyl (E,4S)-4-[(2S,4bS,7S,8aR)-7-hydroxy-2,4b-dimethyl-1-oxo-4,4a,5,6,7,8,8a,9,10,10a-decahydro-3H-phenanthren-2-yl]hex-2-enoate	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.1200	uM
3-[(1S)-1-[(2S,4bS,7S,8aR)-7-hydroxy-2,4b-dimethyl-1,3,4,4a,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-2-yl]propyl]-2H-furan-5-one	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.1300	uM
3-[(1R)-1-[(2R,4bS,7S,8aR)-7-hydroxy-2,4b-dimethyl-1-oxo-4,4a,5,6,7,8,8a,9,10,10a-decahydro-3H-phenanthren-2-yl]propyl]-2H-furan-5-one	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.2000	uM
(5S,8R,9S,10R,13S,14S)-3-(2-aminoethoxyimino)-10,13-dimethyl-1,2,4,5,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-6,17-dione	146859: Inhibitory activity against Na+/K+ ATPase	ic50	0.2000	uM
2-(dimethylamino)ethyl (E,4R)-4-[(2R,4bS,7S,8aR)-7-hydroxy-2,4b-dimethyl-1-oxo-4,4a,5,6,7,8,8a,9,10,10a-decahydro-3H-phenanthren-2-yl]hex-2-enoate	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.2500	uM
methyl (E)-3-[(3S,5R,8R,9S,10S,13R,14S,17R)-3,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]prop-2-enoate	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	0.3500	uM
2-(dimethylamino)ethyl (E)-3-[(3S,5R,8R,9S,10S,13S,14S,17S)-3,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]prop-2-enoate	146857: Compound was evaluated for its ability to inhibit the specific [3H]-ouabain binding to dog kidney Na+/K+ ATPase	ic50	5.8900	uM
(3E,4S,5S,8R,9S,10R,13S,14S)-3-(2-aminoethoxyimino)-4,10,13-trimethyl-1,2,4,5,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-6,17-dione	146859: Inhibitory activity against Na+/K+ ATPase	ic50	6.0000	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression	2
urushiol	increases expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
Sch 28080	affects cotreatment, decreases reaction, increases uptake	1
abrine	increases expression	1
Capecitabine	increases expression	1
Air Pollutants	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Ivermectin	decreases expression	1
Ouabain	affects cotreatment, decreases reaction, increases uptake	1
Rubidium	affects cotreatment, increases uptake, decreases reaction	1
Sodium Dodecyl Sulfate	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	affects methylation	1
Asbestos, Crocidolite	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	increases expression	1
Coal Ash	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 13 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL686817	Binding	Evaluated for the inhibition of H+/K+ ATPase enzyme from fundic mucosa of white rabbits	Synthesis of (aryloxy)alkylamines. 1. Novel antisecretory agents with H+K+-ATPase inhibitory activity. — J Med Chem
CHEMBL690672	Functional	Activity was evaluated by measuring the inhibition of isolated rat H+/K+ ATPase at 10 mg/kg; Inactive	Studies on (H(+)-K+)-ATPase inhibitors of gastric acid secretion. Prodrugs of 2-[(2-pyridinylmethyl)sulfinyl]benzimidazole proton-pump inhibitors. — J Med Chem

Clinical trials (associated diseases)

202 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice