ATP2B3

Summary

ATP2B3 (ATPase plasma membrane Ca2+ transporting 3, HGNC:816) is a protein-coding gene on chromosome Xq28, encoding Plasma membrane calcium-transporting ATPase 3 (Q16720). ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals.

The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 3. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 492 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked progressive cerebellar ataxia (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 261 total — 5 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 31
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_001001344

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:816
Approved symbol	ATP2B3
Name	ATPase plasma membrane Ca2+ transporting 3
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	PMCA3, CFAP39
Ensembl gene	ENSG00000067842
Ensembl biotype	protein_coding
OMIM	300014
Entrez	492

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263519, ENST00000349466, ENST00000359149, ENST00000370186, ENST00000393842, ENST00000496610, ENST00000683064, ENST00000684004, ENST00000705862, ENST00000705863, ENST00000705864, ENST00000868323, ENST00000944046

RefSeq mRNA: 6 — MANE Select: NM_001001344 NM_001001344, NM_001388360, NM_001388361, NM_001388362, NM_001410708, NM_021949

CCDS: CCDS14722, CCDS35440, CCDS94697

Canonical transcript exons

ENST00000263519 — 22 exons

Exon	Start	End
ENSE00000380466	153564921	153565103
ENSE00001100450	153536122	153536455
ENSE00001100455	153556049	153556228
ENSE00001100458	153562135	153562242
ENSE00001100463	153541669	153541926
ENSE00001100466	153541359	153541556
ENSE00001100469	153546088	153546129
ENSE00001100483	153556331	153556418
ENSE00001100484	153547835	153547999
ENSE00001100487	153553035	153553269
ENSE00001100493	153556917	153557023
ENSE00001100496	153549497	153549739
ENSE00001677610	153542323	153542448
ENSE00001730380	153548640	153548854
ENSE00001744793	153550045	153550286
ENSE00001759681	153543043	153543168
ENSE00001768199	153560676	153560887
ENSE00003475625	153559729	153559942
ENSE00003519516	153579978	153582929
ENSE00003563519	153558112	153558303
ENSE00003918078	153518432	153518551
ENSE00003920448	153517642	153517875

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 96.85.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6592 / max 75.1557, expressed in 141 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198076	1.1145	126
198079	0.2590	87
198080	0.1130	65
198077	0.0977	58
198082	0.0419	20
198081	0.0168	6
198078	0.0163	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.85	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.57	gold quality
middle temporal gyrus	UBERON:0002771	94.13	gold quality
primary visual cortex	UBERON:0002436	91.18	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.45	gold quality
cerebellar cortex	UBERON:0002129	88.13	gold quality
cerebellar hemisphere	UBERON:0002245	88.12	gold quality
cerebellum	UBERON:0002037	87.40	gold quality
occipital lobe	UBERON:0002021	86.96	gold quality
frontal pole	UBERON:0002795	86.81	gold quality
superior frontal gyrus	UBERON:0002661	85.94	gold quality
cerebellar vermis	UBERON:0004720	85.32	gold quality
postcentral gyrus	UBERON:0002581	85.14	gold quality
paraflocculus	UBERON:0005351	84.98	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.08	gold quality
Brodmann (1909) area 10	UBERON:0013541	84.08	gold quality
parietal lobe	UBERON:0001872	84.05	gold quality
entorhinal cortex	UBERON:0002728	83.84	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.83	gold quality
right frontal lobe	UBERON:0002810	83.47	gold quality
prefrontal cortex	UBERON:0000451	83.38	gold quality
lateral nuclear group of thalamus	UBERON:0002736	83.27	gold quality
frontal cortex	UBERON:0001870	82.80	gold quality
neocortex	UBERON:0001950	82.29	gold quality
cerebral cortex	UBERON:0000956	81.98	gold quality
right adrenal gland	UBERON:0001233	81.71	gold quality
right adrenal gland cortex	UBERON:0035827	81.35	gold quality
cingulate cortex	UBERON:0003027	80.92	gold quality
anterior cingulate cortex	UBERON:0009835	80.90	gold quality
cortical plate	UBERON:0005343	80.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

114 targeting ATP2B3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-8080	99.82	67.52	1342

Literature-anchored findings (GeneRIF, showing 13)

• role in the intracellular Ca(2+) extrusion of syncytiotrophoblast-like structure originating from the differentiation of cultured trophoblast cells isolated from human term placenta (PMID:12784250)
• Expression of the placental calcium transporter PMCA3 mRNA predicts neonatal whole body bone mineral content (PMID:17336174)
• Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. (PMID:22912398)
• Somatic mutations in ATP2B3 gene leads to aldosterone-producing adenomas and secondary hypertension. (PMID:23416519)
• ATP2B3 mutations are present in aldosterone-producineg adenomas that result in an increase in CYP11B2 gene expression and may account for the dysregulated aldosterone production in a subset of patients with sporadic primary aldosteronism. (PMID:24082052)
• Somatic mutations found in KCNJ5, ATP1A1, and ATP2B3 appear to be the driving forces for a higher aldosterone production and proliferations of glomerulosa cells. (PMID:24179102)
• Novel PMCA3 missense mutation co-occurring with a heterozygous mutation in LAMA1 impaired cellular Ca2+ homeostasis in patients with Cerebellar Ataxia. (PMID:25953895)
• Mutations in ATP2B3 gene is associated with aldosterone-producing adenomas. (PMID:26285814)
• Different mutations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) are found in different aldosterone-producing nodules from the same adrenal, suggesting that somatic mutations are independent events triggered by mechanisms that remain to be identified. (PMID:26351028)
• In summary, the APA-associated ATP2B3(Leu425_Val426del) mutant promotes aldosterone production by at least 2 different mechanisms: 1) a reduced Ca(2+) export due to the loss of the physiological pump function; and 2) an increased Ca(2+) influx due to opening of depolarization-activated Ca(2+) channels as well as a possible Ca(2+) leak through the mutated pump. (PMID:27035656)
• The ataxia related G1107D mutation of the PMCA 3 impairs its calcium pumping function. The mutation affects the interplay of calmodulin with its binding domain on the pump, decreasing its stimulation. (PMID:27632770)
• Authors report a novel PMCA3 mutation (G733R substitution) in the catalytic P-domain of the pump in a patient affected by non-progressive ataxia, muscular hypotonia, dysmetria and nystagmus. (PMID:28807751)
• The ataxia-linked E1081Q mutation affects the sub-plasma membrane Ca(2+)-microdomains by tuning PMCA3 activity. (PMID:36207321)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Atp2b3	ENSMUSG00000031376
rattus_norvegicus	Atp2b3	ENSRNOG00000061304
drosophila_melanogaster	SPoCk	FBGN0052451
drosophila_melanogaster	CG45062	FBGN0266432
drosophila_melanogaster	CG45063	FBGN0266433
caenorhabditis_elegans		WBGENE00000834
caenorhabditis_elegans	pmr-1	WBGENE00004063
caenorhabditis_elegans		WBGENE00015338
caenorhabditis_elegans		WBGENE00015660

Paralogs (21): ATP2C1 (ENSG00000017260), ATP1A2 (ENSG00000018625), ATP2B4 (ENSG00000058668), ATP2C2 (ENSG00000064270), ATP2B1 (ENSG00000070961), ATP2A3 (ENSG00000074370), ATP12A (ENSG00000075673), 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

Plasma membrane calcium-transporting ATPase 3 — Q16720 (reviewed: Q16720)

Alternative names: Plasma membrane calcium ATPase isoform 3, Plasma membrane calcium pump isoform 3

All UniProt accessions (6): Q16720, A0A804HKZ0, A0A994J4Z5, A0A994J581, A0A994J5M1, A0A994J7W3

UniProt curated annotations — full annotation on UniProt →

Function. ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals. Uses ATP as an energy source to transport cytosolic Ca(2+) ions across the plasma membrane to the extracellular compartment. May counter-transport protons, but the mechanism and the stoichiometry of this Ca(2+)/H(+) exchange remains to be established.

Subunit / interactions. Interacts with PDZD11. Interacts (via N-terminus) with YWHAE.

Subcellular location. Cell membrane. Presynaptic cell membrane.

Tissue specificity. Highly expressed in the cerebellum. Expressed in adrenal glands.

Disease relevance. Spinocerebellar ataxia, X-linked 1 (SCAX1) [MIM:302500] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAX1 is characterized by hypotonia at birth, delayed motor development, gait ataxia, difficulty standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar ataxia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Down-regulated by YWHAE.

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

Isoforms (8)

UniProt ID	Names	Canonical?
Q16720-1	XB, AIICI	yes
Q16720-2	XA, AIICII
Q16720-3	ZA, AICII
Q16720-4	ZB, AICI
Q16720-5	XE, AIICV
Q16720-6	ZE, AICV
Q16720-7	XG, AIICVII
Q16720-8	ZG, AICVII

RefSeq proteins (6): NP_001001344, NP_001375289, NP_001375290, NP_001375291, NP_001397637, NP_068768 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001757	P_typ_ATPase	Family
IPR004014	ATPase_P-typ_cation-transptr_N	Domain
IPR006068	ATPase_P-typ_cation-transptr_C	Domain
IPR006408	P-type_ATPase_IIB	Family
IPR008250	ATPase_P-typ_transduc_dom_A_sf	Homologous_superfamily
IPR018303	ATPase_P-typ_P_site	PTM
IPR022141	ATP_Ca_trans_C	Domain
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
IPR059000	ATPase_P-type_domA	Domain

Pfam: PF00122, PF00689, PF00690, PF08282, PF12424, PF13246

Enzyme classification (BRENDA):

• EC 7.2.2.10 — P-type Ca2+ transporter (BRENDA: 47 organisms, 90 substrates, 341 inhibitors, 34 Km, 18 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CA2+	—	11
ATP	—	6
CA2+/CIS	0.0007–0.0013	3
CA2+[SIDE 1]	0.0002–0.0003	2
SR2+	0.015–0.035	2
UTP	—	1

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) + ATP + H2O = Ca(2+)(out) + ADP + phosphate + H(+) (RHEA:18105)

UniProt features (47 total): topological domain 11, transmembrane region 10, region of interest 5, splice variant 4, sequence variant 4, compositionally biased region 3, modified residue 3, binding site 2, sequence conflict 2, chain 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16720-F1	74.57	0.30

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): 473 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (2): 794; 798

Post-translational modifications (3): 8, 1079, 1113

Mutagenesis-validated functional residues (1):

Position	Phenotype
473	impaired atpase activity.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-418359	Reduction of cytosolic Ca++ levels
R-HSA-5578775	Ion homeostasis
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-109582	Hemostasis
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-418346	Platelet homeostasis
R-HSA-418360	Platelet calcium homeostasis
R-HSA-5576891	Cardiac conduction
R-HSA-983712	Ion channel transport

MSigDB gene sets: 192 (showing top): GOBP_CIRCULATORY_SYSTEM_PROCESS, AAGCCAT_MIR135A_MIR135B, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, HEN1_01, HP1SITEFACTOR_Q6, TGACATY_UNKNOWN, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_REGULATION_OF_CYTOSOLIC_CALCIUM_ION_CONCENTRATION, LYF1_01, HNF1_C, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_HEART_PROCESS, GOCC_NEURON_PROJECTION, AGTCAGC_MIR345

GO Biological Process (9): monoatomic ion transmembrane transport (GO:0034220), regulation of cytosolic calcium ion concentration (GO:0051480), regulation of cardiac conduction (GO:1903779), calcium ion export across plasma membrane (GO:1990034), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588), regulation of presynaptic cytosolic calcium ion concentration (GO:0099509)

GO Molecular Function (10): P-type calcium transporter activity (GO:0005388), calmodulin binding (GO:0005516), ATP binding (GO:0005524), calcium ion transmembrane transporter activity (GO:0015085), ATP hydrolysis activity (GO:0016887), metal ion binding (GO:0046872), P-type calcium transporter activity involved in regulation of presynaptic cytosolic calcium ion concentration (GO:1905056), nucleotide binding (GO:0000166), transporter activity (GO:0005215), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), presynaptic membrane (GO:0042734), parallel fiber to Purkinje cell synapse (GO:0098688), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), extracellular vesicle (GO:1903561), parallel fiber (GO:1990032), endomembrane system (GO:0012505), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Platelet calcium homeostasis	1
Cardiac conduction	1
Ion channel transport	1
Hemostasis	1
Platelet homeostasis	1
Muscle contraction	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
calcium ion transmembrane transport	2
transport	2
presynapse	2
synapse	2
monoatomic ion transport	1
transmembrane transport	1
intracellular calcium ion homeostasis	1
regulation of heart contraction	1
cardiac conduction	1
export across plasma membrane	1
metal ion transport	1
cellular process	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
regulation of cytosolic calcium ion concentration	1
neuron cellular homeostasis	1
calcium ion transmembrane transporter activity	1
P-type ion transporter activity	1
ATPase-coupled monoatomic cation transmembrane transporter activity	1
protein binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
metal ion transmembrane transporter activity	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
cation binding	1
P-type calcium transporter activity	1
regulation of presynaptic cytosolic calcium ion concentration	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
membrane	1
cell periphery	1
synaptic membrane	1
excitatory synapse	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP2B3	KCNJ5	P48544	878
ATP2B3	CACNA1D	Q01668	807
ATP2B3	CYP11B2	P19099	763
ATP2B3	CALM1	P02593	719
ATP2B3	CALML3	P27482	717
ATP2B3	CALML5	Q9NZT1	717
ATP2B3	CACNA1H	O95180	708
ATP2B3	CALML6	Q8TD86	704
ATP2B3	CALML4	Q96GE6	704
ATP2B3	ARMC5	Q96C12	665
ATP2B3	CLCN2	P51788	634
ATP2B3	CYP11B1	P15538	621
ATP2B3	VTN	P01141	511
ATP2B3	SCARB1	Q8WTV0	502
ATP2B3	SCARB2	Q14108	493

IntAct

82 interactions, top by confidence:

A	B	Type	Score
PRKAG1	PRKAB2	psi-mi:“MI:0914”(association)	0.940
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
RANBP6	SLC27A2	psi-mi:“MI:0914”(association)	0.640
FOXR1	MYC	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
GALNT6	NDUFS4	psi-mi:“MI:0914”(association)	0.530
HSD17B6	NME2P1	psi-mi:“MI:0914”(association)	0.530
TSPAN5	SC5D	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NPTN	TNPO2	psi-mi:“MI:0914”(association)	0.530
ATP2B3	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
ATP2B3	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
ATP2B3	H2AC4	psi-mi:“MI:0915”(physical association)	0.400
ATP2B3	HTR2C	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
ATP2B1	ACSL3	psi-mi:“MI:0914”(association)	0.350
ATP2B2	ESYT2	psi-mi:“MI:0914”(association)	0.350
AVPR2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LRRC55	TMEM120B	psi-mi:“MI:0914”(association)	0.350
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
CSGALNACT1	FAM234B	psi-mi:“MI:0914”(association)	0.350

BioGRID (129): ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS)

ESM2 similar proteins: A0A143ZZK9, A5IYF2, A6ZQM4, B3LQ11, B9QMJ0, B9WLN5, D3K0R6, G5E829, G5EFR6, J9VQQ3, O13397, O13398, P11505, P11506, P13586, P13587, P20020, P22189, P23220, P23634, P32660, P38929, P39677, P54678, P54679, P58165, Q00804, Q01814, Q01896, Q06698, Q12675, Q12691, Q16720, Q54L53, Q54SW3, Q54TV1, Q54TV2, Q55CP6, Q5A6N1, Q64542

Diamond homologs: A0A0P0X004, A0AM16, B0R9M0, B2TMJ2, B2V2P3, B8DAW1, C1KZN5, D3K0R6, G0S196, G5E829, G5EFR6, J9VQQ3, O22218, O29777, O31688, O32328, O54827, O60312, O64806, O81108, P11505, P11506, P20020, P23220, P23634, P28774, P35317, P37279, P37367, P38929, P38995, P54678, P57698, P57699, P57700, P58165, P58342, P86911, P9WPS2, P9WPS3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 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
Platelet calcium homeostasis	5	37.6×	4e-05
Platelet homeostasis	6	17.6×	2e-04
Ion transport by P-type ATPases	6	13.1×	7e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	11.4×	4e-04
Ion homeostasis	5	10.7×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cytosolic calcium ion concentration	5	16.2×	3e-03
regulation of heart rate by cardiac conduction	5	15.9×	3e-03
phospholipase C-activating G protein-coupled receptor signaling pathway	8	8.9×	3e-03
positive regulation of cytosolic calcium ion concentration	8	7.9×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — BRCA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	137
Likely benign	65
Benign	26

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
162467	NM_001001344.3(ATP2B3):c.1272_1277del (p.Leu425_Val426del)	Pathogenic
162469	NM_001001344.3(ATP2B3):c.1273_1278del (p.Leu425_Val426del)	Pathogenic
162470	NM_001001344.3(ATP2B3):c.1277_1282del (p.Val426_Val427del)	Pathogenic
265796	BGN, 21-KB DEL (SCV000266570)	Pathogenic
997082	GRCh37/hg19 Xq28(chrX:152649825-152988014)	Pathogenic
1027532	NM_001001344.3(ATP2B3):c.130G>A (p.Glu44Lys)	Likely pathogenic
1098287	NM_001001344.3(ATP2B3):c.2770A>G (p.Thr924Ala)	Likely pathogenic
225046	NM_001001344.3(ATP2B3):c.3338C>T (p.Thr1113Met)	Likely pathogenic
242886	NM_001001344.3(ATP2B3):c.3594G>T (p.Lys1198Asn)	Likely pathogenic
39839	NM_001001344.3(ATP2B3):c.3320G>A (p.Gly1107Asp)	Likely pathogenic
692299	NM_001001344.3(ATP2B3):c.197C>T (p.Ser66Leu)	Likely pathogenic

SpliceAI

4382 predictions. Top by Δscore:

Variant	Effect	Δscore
X:153517874:GG:G	donor_gain	1.0000
X:153517875:GG:G	donor_gain	1.0000
X:153517875:GGTA:G	donor_loss	1.0000
X:153517876:G:GG	donor_gain	1.0000
X:153517877:T:A	donor_loss	1.0000
X:153541336:T:TA	acceptor_gain	1.0000
X:153541344:C:CA	acceptor_gain	1.0000
X:153541345:G:A	acceptor_gain	1.0000
X:153541553:GAAG:G	donor_gain	1.0000
X:153541554:AAGG:A	donor_loss	1.0000
X:153541555:AGGTA:A	donor_loss	1.0000
X:153541556:GGTA:G	donor_loss	1.0000
X:153541557:GTAAG:G	donor_loss	1.0000
X:153541655:T:A	acceptor_gain	1.0000
X:153541662:C:CA	acceptor_gain	1.0000
X:153541664:CACA:C	acceptor_loss	1.0000
X:153541665:A:AG	acceptor_gain	1.0000
X:153541665:ACAG:A	acceptor_loss	1.0000
X:153541666:CA:C	acceptor_loss	1.0000
X:153541667:A:AG	acceptor_gain	1.0000
X:153541667:AGCCT:A	acceptor_gain	1.0000
X:153541668:G:GG	acceptor_gain	1.0000
X:153541668:GC:G	acceptor_gain	1.0000
X:153541668:GCC:G	acceptor_gain	1.0000
X:153541668:GCCT:G	acceptor_gain	1.0000
X:153541668:GCCTG:G	acceptor_gain	1.0000
X:153541922:GTACG:G	donor_gain	1.0000
X:153541926:GGTGA:G	donor_loss	1.0000
X:153541927:G:GG	donor_gain	1.0000
X:153541927:GTGAG:G	donor_loss	1.0000

AlphaMissense

8023 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:153541482:T:A	L111H	1.000
X:153541482:T:C	L111P	1.000
X:153541491:T:A	L114Q	1.000
X:153541491:T:C	L114P	1.000
X:153541500:C:A	A117D	1.000
X:153541503:C:A	A118D	1.000
X:153541515:T:C	L122P	1.000
X:153541722:T:A	W154R	1.000
X:153541722:T:C	W154R	1.000
X:153541731:G:A	G157R	1.000
X:153541731:G:C	G157R	1.000
X:153541731:G:T	G157W	1.000
X:153541738:C:A	A159D	1.000
X:153541741:T:A	I160N	1.000
X:153541741:T:C	I160T	1.000
X:153541741:T:G	I160S	1.000
X:153541777:C:A	A172D	1.000
X:153541796:G:C	K178N	1.000
X:153541796:G:T	K178N	1.000
X:153541806:T:C	F182L	1.000
X:153541808:C:A	F182L	1.000
X:153541808:C:G	F182L	1.000
X:153542395:G:A	G246D	1.000
X:153543099:T:C	S283P	1.000
X:153543124:T:C	L291P	1.000
X:153547955:T:A	L360H	1.000
X:153547955:T:C	L360P	1.000
X:153547967:T:A	L364H	1.000
X:153547967:T:C	L364P	1.000
X:153547976:T:C	L367P	1.000

dbSNP variants (sampled 300 via entrez): RS1000069005 (X:153544347 C>T), RS1000107038 (X:153551717 T>C), RS1000370052 (X:153565838 C>T), RS1000410485 (X:153544759 A>G), RS1000445249 (X:153565588 C>A,T), RS1000490303 (X:153518536 G>A), RS1000591289 (X:153526336 G>A), RS1000598836 (X:153572588 C>T), RS1000624032 (X:153526124 G>A), RS1000661530 (X:153579453 G>A), RS1000686645 (X:153558351 G>T), RS1000713261 (X:153579131 C>A), RS1000789404 (X:153539281 T>C), RS1000819871 (X:153518938 C>T), RS1000859780 (X:153538907 C>A,T)

Disease associations

OMIM: gene MIM:300014 | disease phenotypes: MIM:108600, MIM:302500, MIM:300352, MIM:300989, MIM:607086, MIM:617468, MIM:208150, MIM:312750

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked progressive cerebellar ataxia	Strong	X-linked
X-linked non progressive cerebellar ataxia	Supportive	X-linked

Mondo (15): spastic ataxia (MONDO:0017845), X-linked progressive cerebellar ataxia (MONDO:0010547), aldosterone-producing adrenal cortex adenoma (MONDO:0016505), creatine transporter deficiency (MONDO:0010305), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), muscular atrophy (MONDO:0004323), dental caries (MONDO:0005276), neurodevelopmental disorder (MONDO:0700092), Meester-Loeys syndrome (MONDO:0010515), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), Rett syndrome (MONDO:0010726), X-linked non progressive cerebellar ataxia (MONDO:0010404)

Orphanet (10): Spastic ataxia (Orphanet:316226), X-linked progressive cerebellar ataxia (Orphanet:1175), Adrenocortical carcinoma with pure aldosterone hypersecretion (Orphanet:231625), X-linked creatine transporter deficiency (Orphanet:52503), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), Atypical Rett syndrome (Orphanet:3095), Rett syndrome (Orphanet:778), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000486	Strabismus
HP:0000514	Slow saccadic eye movements
HP:0000639	Nystagmus
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001319	Neonatal hypotonia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001419	X-linked recessive inheritance
HP:0002015	Dysphagia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002078	Truncal ataxia
HP:0002080	Intention tremor
HP:0002312	Clumsiness
HP:0002317	Unsteady gait
HP:0002345	Action tremor
HP:0002359	Frequent falls
HP:0002464	Spastic dysarthria
HP:0002470	Nonprogressive cerebellar ataxia
HP:0003487	Babinski sign
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003680	Nonprogressive
HP:0003698	Difficulty standing

GWAS associations

0 associations (top):

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D003731	Dental Caries	C07.793.720.210
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009133	Muscular Atrophy	C10.597.613.612; C23.300.070.500; C23.888.592.608.612
D065886	Neurodevelopmental Disorders	F03.625
D015518	Rett Syndrome	C10.597.606.360.455.937; C16.320.322.500.937; C16.320.400.525.937
C535598	Creatine deficiency, X-linked (supp.)
C564815	Spastic Ataxia (supp.)
C563134	Spinocerebellar Ataxia, X-Linked 1 (supp.)
C567478	Spinocerebellar Ataxia, X-Linked 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — P2B P-type ATPases: Ca²⁺-ATPases

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
bisphenol A	affects cotreatment, increases methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
clothianidin	decreases expression	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation	1
Catechin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Lead	affects expression	1
Malathion	decreases expression	1
Methapyrilene	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	decreases expression	1
Antirheumatic Agents	increases expression	1
Coal Ash	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00018356	PHASE4	COMPLETED	Physiologic Effects of PRMS & Testosterone in the Debilitated Elderly
NCT02568020	PHASE4	UNKNOWN	LPD+α-ketoacids on Autophagy and Improving Muscle Wasting in CKD
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01373697	PHASE3	UNKNOWN	Study to Assess the Efficacy and Safety of Ibuprofen 50 mg/g Gel Compared to Profenid 25mg/g Gel
NCT01595581	PHASE3	COMPLETED	Testosterone Administration and ACL Reconstruction in Men
NCT03054168	PHASE3	UNKNOWN	Systemic Hormones and Muscle Protein Synthesis
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00475501	PHASE2	COMPLETED	5-Alpha Reductase and Anabolic Effects of Testosterone
NCT00787098	PHASE2	COMPLETED	Investigating Modes of Progressive Mobility
NCT01369511	PHASE2	COMPLETED	A Study of LY2495655 in Older Participants Undergoing Elective Total Hip Replacement
NCT02145949	PHASE2	COMPLETED	Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults
NCT03332238	PHASE2	ACTIVE_NOT_RECRUITING	Stromal Vascular Fraction Cell Therapy to Improve the Repair of Rotator Cuff Tears
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT04742010	PHASE2	UNKNOWN	Zoledronic Acid for Prevention of Bone Loss After BAriatric Surgery (ZABAS)
NCT05198466	PHASE2	COMPLETED	Electrical Stimulation for Critically Ill Post-Covid-19 Patients
NCT06050668	PHASE2	RECRUITING	Essential Amino Acid Supplementation for Femoral Fragility Fractures
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00952887	PHASE1	COMPLETED	A Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of ACE-031 in Healthy Postmenopausal Women
NCT01524406	PHASE1	TERMINATED	Safety Study of HPP593 in Subjects During and After Limb Immobilization
NCT04685213	PHASE1	COMPLETED	Electrical Stimulation for Critically Ill Covid-19 Patients
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT02931682	Not specified	TERMINATED	Observational Study of Males With Creatine Transporter Deficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05642221	Not specified	COMPLETED	Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls
NCT06139172	Not specified	RECRUITING	Web Intervention for Parents of Youth With Genetic Syndromes (WINGS)
NCT06292884	Not specified	UNKNOWN	Optical Imaging as a Tool for Monitoring Brain Function in Creatine Deficiency Syndromes