ATP2B4

Summary

ATP2B4 (ATPase plasma membrane Ca2+ transporting 4, HGNC:817) is a protein-coding gene on chromosome 1q32.1, encoding Plasma membrane calcium-transporting ATPase 4 (P23634). Calcium/calmodulin-regulated and magnesium-dependent enzyme that catalyzes the hydrolysis of ATP coupled with the transport of calcium out of the cell.

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 4. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 493 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia (Moderate, GenCC)
• GWAS associations: 34
• Clinical variants (ClinVar): 326 total
• MANE Select transcript: NM_001684

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:817
Approved symbol	ATP2B4
Name	ATPase plasma membrane Ca2+ transporting 4
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	PMCA4
Ensembl gene	ENSG00000058668
Ensembl biotype	protein_coding
OMIM	108732
Entrez	493

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000341360, ENST00000356729, ENST00000357681, ENST00000458092, ENST00000466407, ENST00000484746, ENST00000705901, ENST00000890814, ENST00000890815, ENST00000890816, ENST00000935435, ENST00000943661

RefSeq mRNA: 4 — MANE Select: NM_001684 NM_001001396, NM_001365783, NM_001365784, NM_001684

CCDS: CCDS1440, CCDS30977

Canonical transcript exons

ENST00000357681 — 21 exons

Exon	Start	End
ENSE00000545354	203722478	203722689
ENSE00000791584	203714171	203714277
ENSE00000791588	203723881	203723988
ENSE00000828762	203713165	203713252
ENSE00000828771	203727395	203727571
ENSE00001075115	203698157	203698354
ENSE00001075118	203709301	203709542
ENSE00001075119	203707862	203708104
ENSE00001075120	203699460	203699717
ENSE00001075121	203700798	203700923
ENSE00001075122	203710877	203711108
ENSE00001075132	203703652	203703813
ENSE00001075135	203702044	203702079
ENSE00001075137	203700206	203700331
ENSE00001129421	203711960	203712139
ENSE00001443849	203682742	203683398
ENSE00001601399	203720549	203720740
ENSE00001679711	203739546	203744081
ENSE00001764544	203707009	203707223
ENSE00001799826	203721197	203721410
ENSE00003994333	203626832	203627219

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.29.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.3105 / max 385.3865, expressed in 154 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7911	33.8429	1762
7910	13.2521	1758
7917	8.7657	1290
41054	4.3105	154
7912	2.7600	1011
7916	1.5350	818
7915	1.5044	877
7914	1.1143	549
7913	0.9074	557
7919	0.8844	517

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	99.29	gold quality
cauda epididymis	UBERON:0004360	98.92	gold quality
body of uterus	UBERON:0009853	98.79	gold quality
myometrium	UBERON:0001296	98.72	gold quality
colonic epithelium	UBERON:0000397	98.62	gold quality
smooth muscle tissue	UBERON:0001135	98.31	gold quality
left uterine tube	UBERON:0001303	98.27	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.21	gold quality
superficial temporal artery	UBERON:0001614	98.17	gold quality
upper arm skin	UBERON:0004263	98.14	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.03	gold quality
lower esophagus	UBERON:0013473	98.00	gold quality
urethra	UBERON:0000057	97.99	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.96	gold quality
pericardium	UBERON:0002407	97.94	gold quality
nipple	UBERON:0002030	97.93	gold quality
pylorus	UBERON:0001166	97.88	gold quality
vena cava	UBERON:0004087	97.88	gold quality
decidua	UBERON:0002450	97.76	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.73	gold quality
synovial joint	UBERON:0002217	97.52	gold quality
cartilage tissue	UBERON:0002418	97.41	gold quality
right coronary artery	UBERON:0001625	97.39	gold quality
myocardium	UBERON:0002349	97.25	gold quality
uterus	UBERON:0000995	97.19	gold quality
left ventricle myocardium	UBERON:0006566	97.18	gold quality
trigeminal ganglion	UBERON:0001675	97.10	gold quality
lower lobe of lung	UBERON:0008949	97.10	gold quality
mammalian vulva	UBERON:0000997	97.07	gold quality
mucosa of stomach	UBERON:0001199	97.07	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	4.99
E-MTAB-6075	no	575.64
E-GEOD-106540	no	257.04
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
PTGS2	Repression
RCAN1	Repression

Upstream regulators (CollecTRI, top): AR, ESR1

miRNA regulators (miRDB)

287 targeting ATP2B4, 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-5193	100.00	67.26	1744
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821

Literature-anchored findings (GeneRIF, showing 40)

• We demonstrate here that, in the early phase of apoptosis, hPMCA4b is cleaved at aspartic acid Asp(1080) in hPMCA4b-transfected COS-7 cells or in HeLa cells that naturally express this protein (PMID:11751908)
• plasma membrane Ca2+ pump 4b/CI binds to Ca2+/calmodulin-dependent membrane-associated kinase CASK (PMID:12511555)
• co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. (PMID:12540962)
• 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)
• results suggest that a decrease in PMCA4b expression in Meg-01 cells is compensated to maintain normal intracellular calcium levels. (PMID:12944246)
• functional association with RASSF1 indicates a role for PMCA4b in the modulation of Ras-mediated signaling (PMID:15145946)
• residue Asp(170), in the putative “A” domain of human PMCA isoform 4xb, plays a critical role in autoinhibition (PMID:15292209)
• a novel functional interaction between PMCA and calcineurin, suggesting a role for PMCA as a negative modulator of calcineurin-mediated signaling pathways in mammalian cells. (PMID:15955804)
• The characteristics of the fragment of hPMCA4b produced by caspase-3 are reported. (PMID:16080782)
• Although differences in PMCA4 mRNA levels were observed between breast cell lines, they were not of the magnitude observed for PMCA2. (PMID:16216224)
• PMCA activity is influenced by membrane lipid composition and structure. The naturally high degree of lipid order in plasma membranes such as those found in human lens may serve to support PMCA activity. (PMID:16412504)
• found abnormal expression of both PMCA and SERCA-type CA2+-ATPases in platelets of patients with adolescent idiopathic scoliosis (PMID:16973504)
• PMCA4 is a good housekeeping gene for normalization of gene expression for polytopic membrane proteins including transporters and receptors. (PMID:16978418)
• physiological relevance of the interaction between PMCA4b and nNOS and suggests its signaling role in the heart (PMID:17242280)
• PMCA4b is localized in non-filamentous actin complexes in resting platelets by means of PDZ domain interactions and then associates with the actin cytoskeleton during cytoskeletal rearrangement upon platelet activation. (PMID:17393022)
• Compared with the expression of PMCA4b upon platelet maturation, platelets from diabetic patients exhibit similarities with immature megakaryocytes (PMID:17883705)
• platelets in hypertensive patients demonstrated a major increase in plasma membrane Ca(2+)ATPase 4b (PMCA4b) expression when compared with normal controls (PMID:17957572)
• PMCA4 seems to be preferentially distributed in both human syncytiotrophoblast plasma membranes. (PMID:18657858)
• This protein has been found differentially expressed in patients with schizophrenia. (PMID:19034380)
• Results suggest that PSD-95 promotes the formation of high-density PMCA4b microdomains in the plasma membrane and that the membrane cytoskeleton plays an important role in the regulation of this process. (PMID:19073225)
• Pmca4b likely reduces the local Ca2+ signals involved in reactive cardiomyocyte hypertrophy via calcineurin regulation. (PMID:19287093)
• PMCA4 is significantly (P < 0.000001) downregulated early in the progression of some colon cancers as these cells become less differentiated (PMID:19755660)
• Data show that the anchors correspond to Phe-1110 and Trp-1093, respectively, in full-length PMCA4b, and the peptide and CaM are oriented in an anti-parallel manner. (PMID:19996092)
• Report a novel interaction between endogenous plasma membrane calcium ATPase (PMCA) and eNOS in endothelial cells. PMCA may negatively modulate eNOS activity, and NO-dependent signal transduction pathways. (PMID:20211863)
• regulatory domain works independently of its terminal localization and if auto-inhibitory domains (PMID:21073872)
• PMCA4 is strongly expressed in rabbit CE and its immunolocalization exhibits marked changes in distribution during the wound healing process. (PMID:21139678)
• The recently emerging role of the plasma membrane calcium/calmodulin dependent ATPase isoform 4 (PMCA4) in regulating calcium signalling, is reviewed. (PMID:21167220)
• The results of this study suggest posttranscriptional regulation of PMCA4 during carcinogenesis. (PMID:22480210)
• GUSB and ATP2B4 have been validated as a reliable gene combination for Cystic Fibrosis Transmembrane Conductance Regulator gene qPCR data normalization. (PMID:22525089)
• Alternative pathways for association and dissociation of the calmodulin-binding domain of plasma membrane Ca(2+)-ATPase isoform 4b (PMCA4b). (PMID:22767601)
• Genome-wide association study for severe malaria identified a locus on chromosome 1q32 within the ATP2B4 gene, and another locus on chromosome 16q22.2, possibly linked to a neighbouring gene encoding the tight-junction protein MARVELD3 (PMID:22895189)
• High PMCA4 gene expression correlates with high peak bone mass in humans. (PMID:23266958)
• An ATP2B4 variant reduces the odds of P. falciparum infection in pregnancy and mitigates the odds of associated maternal anemia. (PMID:23444010)
• The PMCA4b enriched in lipid rafts decreases the local [Ca2+] levels, downregulating the nNOS activity dynamically associated to PMCA4b via Ca2+-dependent PDZ domain-mediated protein- protein interactions. (PMID:23549614)
• a di-leucine-like internalization signal at the C-tail of PMCA4b, is reported. (PMID:23830917)
• A significant relationship between ATP2B4 gene expression and the tumor location was detected in patients with rectum tumors. (PMID:24583174)
• No significant relationship was detected in the level of expression of the ATP2B4 and ATP5B genes in cancerous and healthy tissues of colorectal cancer patients. (PMID:24583174)
• Calcium dysregulation resulting from a novel missense mutation (c.803G>A, p.R268Q) in the PMCA4 (ATP2B4) gene may be associated with the pathogenesis of familial spastic paraplegia. (PMID:25119969)
• PMCA4 inhibits the activation of the calcineurin/NFAT pathway on VEGF stimulation of endothelial cells, leading to a significant attenuation of VEGF-mediated angiogenesis. (PMID:25147342)
• Mechanism of PMCA4 that creates lipid asymmetry is well understood in terms of ATP hydrolysis; molecular models exist for trajectory taken by phospholipid substrates through the enzyme. [review-like article] (PMID:25233416)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp2b4	ENSDARG00000044902
mus_musculus	Atp2b4	ENSMUSG00000026463
rattus_norvegicus	Atp2b4	ENSRNOG00000003031
drosophila_melanogaster	PMCA	FBGN0259214
caenorhabditis_elegans		WBGENE00000834
caenorhabditis_elegans		WBGENE00015338
caenorhabditis_elegans		WBGENE00015660

Paralogs (21): ATP2C1 (ENSG00000017260), ATP1A2 (ENSG00000018625), ATP2C2 (ENSG00000064270), ATP2B3 (ENSG00000067842), 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 4 — P23634 (reviewed: P23634)

Alternative names: Matrix-remodeling-associated protein 1, Plasma membrane calcium ATPase isoform 4, Plasma membrane calcium pump isoform 4

All UniProt accessions (4): P23634, H0YDG5, H7BY13, H7BZS8

UniProt curated annotations — full annotation on UniProt →

Function. Calcium/calmodulin-regulated and magnesium-dependent enzyme that catalyzes the hydrolysis of ATP coupled with the transport of calcium out of the cell. By regulating sperm cell calcium homeostasis, may play a role in sperm motility.

Subunit / interactions. Interacts with PDZD11. Interacts with SLC35G1 and STIM1. Interacts with calmodulin.

Subcellular location. Cell membrane. Cell projection. Cilium. Flagellum membrane.

Tissue specificity. Isoform XB is the most abundant isoform and is expressed ubiquitously. Isoforms containing segment Z have only been detected in heart, while isoforms containing segment a have been found in heart, stomach and brain cortex.

Activity regulation. Activated by calcium/calmodulin.

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

Isoforms (8)

UniProt ID	Names	Canonical?
P23634-1	XD, AIICIV	yes
P23634-2	XA, AIICII
P23634-3	ZA, AICII
P23634-4	XK, XG
P23634-5	ZK, ZG
P23634-6	XB, AIICI, hPMCA4b
P23634-7	ZB, AICI
P23634-8	ZD, AICIV

RefSeq proteins (4): NP_001001396, NP_001352712, NP_001352713, NP_001675* (*=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

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (50 total): topological domain 11, transmembrane region 10, sequence conflict 7, mutagenesis site 5, splice variant 4, region of interest 3, modified residue 3, binding site 2, turn 2, chain 1, active site 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1CFF	SOLUTION NMR
2KNE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23634-F1	72.71	0.22

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): 465 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (2): 785; 789

Post-translational modifications (3): 13, 328, 1102

Mutagenesis-validated functional residues (5):

Position	Phenotype
672	strongly decreased calcium transport activity. slowed decomposition of the phosphorylated intermediate.
674	decreased calcium transport activity.
675	decreased calcium transport activity.
686	decreased calcium transport activity.
693	mildly decreased calcium transport 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: 803 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_ACID_CHEMICAL, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, TTCCGTT_MIR191, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, CMYB_01, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS

GO Biological Process (35): neural retina development (GO:0003407), regulation of transcription by RNA polymerase II (GO:0006357), intracellular calcium ion homeostasis (GO:0006874), spermatogenesis (GO:0007283), negative regulation of gene expression (GO:0010629), urinary bladder smooth muscle contraction (GO:0014832), negative regulation of angiogenesis (GO:0016525), hippocampus development (GO:0021766), flagellated sperm motility (GO:0030317), monoatomic ion transmembrane transport (GO:0034220), nitric oxide-cGMP-mediated signaling (GO:0038060), negative regulation of blood vessel endothelial cell migration (GO:0043537), negative regulation of nitric oxide biosynthetic process (GO:0045019), regulation of cytosolic calcium ion concentration (GO:0051480), response to hydrostatic pressure (GO:0051599), calcium ion transmembrane transport (GO:0070588), negative regulation of calcineurin-NFAT signaling cascade (GO:0070885), cellular response to epinephrine stimulus (GO:0071872), negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway (GO:0071878), calcium ion transmembrane import into cytosol (GO:0097553), calcium ion import across plasma membrane (GO:0098703), negative regulation of the force of heart contraction (GO:0098736), transport across blood-brain barrier (GO:0150104), negative regulation of arginine catabolic process (GO:1900082), calcium ion export (GO:1901660), regulation of sodium ion transmembrane transport (GO:1902305), negative regulation of cellular response to vascular endothelial growth factor stimulus (GO:1902548), regulation of cell cycle G1/S phase transition (GO:1902806), positive regulation of protein localization to plasma membrane (GO:1903078), negative regulation of cardiac muscle hypertrophy in response to stress (GO:1903243), negative regulation of citrulline biosynthetic process (GO:1903249), regulation of cardiac conduction (GO:1903779), cellular response to acetylcholine (GO:1905145), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816)

GO Molecular Function (16): 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), sodium channel regulator activity (GO:0017080), protein kinase binding (GO:0019901), PDZ domain binding (GO:0030165), protein phosphatase 2B binding (GO:0030346), nitric-oxide synthase inhibitor activity (GO:0036487), metal ion binding (GO:0046872), nitric-oxide synthase binding (GO:0050998), scaffold protein binding (GO:0097110), nucleotide binding (GO:0000166), transporter activity (GO:0005215), protein binding (GO:0005515)

GO Cellular Component (18): mitochondrion (GO:0005739), plasma membrane (GO:0005886), caveola (GO:0005901), cilium (GO:0005929), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), Z disc (GO:0030018), T-tubule (GO:0030315), protein-containing complex (GO:0032991), ciliary basal body (GO:0036064), sperm flagellum (GO:0036126), membrane raft (GO:0045121), presynaptic active zone membrane (GO:0048787), sperm principal piece (GO:0097228), glutamatergic synapse (GO:0098978), motile cilium (GO:0031514), sarcolemma (GO:0042383), cell projection (GO:0042995)

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	5
anatomical structure development	2
calcium ion transmembrane transport	2
protein binding	2
cilium	2
retina development in camera-type eye	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
developmental process involved in reproduction	1
male gamete generation	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
urinary tract smooth muscle contraction	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
pallium development	1
limbic system development	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
monoatomic ion transport	1
transmembrane transport	1
intracellular signaling cassette	1
negative regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
nitric oxide biosynthetic process	1
negative regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
intracellular calcium ion homeostasis	1
response to stress	1
response to water	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1

Protein interactions and networks

STRING

2636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP2B4	CDH23	Q9H251	798
ATP2B4	SNTA1	Q13424	771
ATP2B4	SCN5A	Q14524	771
ATP2B4	OTOP1	Q7RTM1	703
ATP2B4	OC90	Q02509	697
ATP2B4	NOS1	P29475	691
ATP2B4	PCDH15	Q96QU1	689
ATP2B4	CD22	P20273	674
ATP2B4	NHERF2	Q15599	664
ATP2B4	SH3BP5	O60239	639
ATP2B4	PDCD11	Q14690	614
ATP2B4	MYO7A	P78427	589
ATP2B4	CALM1	P02593	588
ATP2B4	RNLS	Q5VYX0	576
ATP2B4	SLC26A4	O43511	569

IntAct

450 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RXYLT1	FKTN	psi-mi:“MI:0914”(association)	0.710
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
MAGI2	ATP2B4	psi-mi:“MI:0407”(direct interaction)	0.610
ATP2B4	DLG4	psi-mi:“MI:0407”(direct interaction)	0.610
ATP2B4	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.610
SCRIB	ATP2B4	psi-mi:“MI:0407”(direct interaction)	0.610
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
PTGER3	PIK3R2	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	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
EDA2R	ICAM1	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
NPTN	TNPO2	psi-mi:“MI:0914”(association)	0.530
DLK1	SCAMP3	psi-mi:“MI:0914”(association)	0.530

BioGRID (282): ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), ATP2B4 (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 234 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
Ras activation upon Ca2+ influx through NMDA receptor	5	18.3×	9e-04
VEGFR2 mediated cell proliferation	5	18.3×	9e-04
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	16.6×	1e-03
RAS processing	5	15.2×	2e-03
NCAM signaling for neurite out-growth	7	12.2×	6e-04
Downstream signal transduction	5	12.2×	2e-03
DAP12 signaling	5	11.8×	3e-03
RAF activation	5	10.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of calcium-mediated signaling	5	27.7×	3e-04
positive regulation of cytosolic calcium ion concentration	15	8.7×	4e-07
calcium-mediated signaling	9	8.1×	5e-04
phospholipase C-activating G protein-coupled receptor signaling pathway	12	7.8×	4e-05
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	7	7.5×	7e-03
chemotaxis	9	6.0×	4e-03
G protein-coupled receptor signaling pathway	21	3.8×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	180
Likely benign	78
Benign	30

Top pathogenic / likely-pathogenic (0)

SpliceAI

3375 predictions. Top by Δscore:

Variant	Effect	Δscore
1:203698154:CA:C	acceptor_loss	1.0000
1:203698155:A:C	acceptor_loss	1.0000
1:203698156:GGT:G	acceptor_gain	1.0000
1:203698156:GGTCT:G	acceptor_gain	1.0000
1:203698350:TGAAC:T	donor_gain	1.0000
1:203698351:GAAC:G	donor_gain	1.0000
1:203698351:GAACG:G	donor_gain	1.0000
1:203698352:AAC:A	donor_gain	1.0000
1:203698353:AC:A	donor_gain	1.0000
1:203698353:ACGT:A	donor_loss	1.0000
1:203698354:CGTG:C	donor_loss	1.0000
1:203698355:G:GG	donor_gain	1.0000
1:203698355:GTGA:G	donor_loss	1.0000
1:203699452:T:TA	acceptor_gain	1.0000
1:203699453:G:A	acceptor_gain	1.0000
1:203699457:TA:T	acceptor_loss	1.0000
1:203699458:A:AG	acceptor_gain	1.0000
1:203699458:AGT:A	acceptor_gain	1.0000
1:203699458:AGTGT:A	acceptor_gain	1.0000
1:203699459:G:GG	acceptor_gain	1.0000
1:203699459:GT:G	acceptor_gain	1.0000
1:203699459:GTG:G	acceptor_gain	1.0000
1:203699459:GTGT:G	acceptor_gain	1.0000
1:203699459:GTGTG:G	acceptor_gain	1.0000
1:203699697:A:AG	donor_gain	1.0000
1:203699716:CGG:C	donor_loss	1.0000
1:203699718:G:GG	donor_gain	1.0000
1:203699719:T:A	donor_loss	1.0000
1:203700196:T:A	acceptor_gain	1.0000
1:203700198:T:TA	acceptor_gain	1.0000

AlphaMissense

7937 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000007815 (1:203684700 T>C,G), RS1000026897 (1:203638237 G>A), RS1000030274 (1:203722333 C>A), RS1000050950 (1:203659863 C>T), RS1000065561 (1:203681480 G>A,T), RS1000109147 (1:203646592 A>G), RS1000109557 (1:203665886 G>T), RS1000167034 (1:203714861 T>A,C), RS1000184564 (1:203723750 T>G), RS1000205147 (1:203638539 C>G,T), RS1000263146 (1:203695084 T>G), RS1000302138 (1:203631528 C>A,T), RS1000307187 (1:203732484 AG>A), RS1000322589 (1:203713274 G>A), RS1000340827 (1:203625139 T>C)

Disease associations

OMIM: gene MIM:108732 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia	Moderate	Autosomal dominant

Mondo (2): prostate cancer (MONDO:0008315), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST001585_38	Breast size	3.000000e-06
GCST001637_2	Malaria	2.000000e-10
GCST001782_6	Mean corpuscular hemoglobin concentration	9.000000e-08
GCST003673_4	Obstructive sleep apnea (average oxygen saturation during sleep)	2.000000e-07
GCST004329_6	Mean corpuscular hemoglobin concentration	2.000000e-06
GCST004602_23	Mean corpuscular volume	1.000000e-14
GCST004605_56	Mean corpuscular hemoglobin concentration	5.000000e-59
GCST004615_83	Hemoglobin concentration	6.000000e-11
GCST004621_41	Red cell distribution width	1.000000e-27
GCST004627_133	Lymphocyte count	3.000000e-10
GCST006804_102	Red cell distribution width	3.000000e-20
GCST008570_5	Composite immunoglobulin trait (IgA x IgG/IgM)	2.000000e-08
GCST010083_261	Hemoglobin levels	4.000000e-30
GCST010725_76	Malaria	9.000000e-08
GCST010725_83	Malaria	1.000000e-11
GCST90000025_841	Appendicular lean mass	4.000000e-15
GCST90002384_21	Hemoglobin	8.000000e-29
GCST90002387_240	Immature fraction of reticulocytes	1.000000e-15
GCST90002388_640	Lymphocyte count	5.000000e-28
GCST90002391_124	Mean corpuscular hemoglobin concentration	3.000000e-70
GCST90002392_247	Mean corpuscular volume	8.000000e-23
GCST90002393_172	Monocyte count	1.000000e-09
GCST90002400_535	Plateletcrit	4.000000e-12
GCST90002403_57	Red blood cell count	6.000000e-25
GCST90002404_440	Red cell distribution width	2.000000e-79
GCST90002405_95	Reticulocyte count	1.000000e-21
GCST90002406_117	Reticulocyte fraction of red cells	3.000000e-14
GCST90002407_21	White blood cell count	2.000000e-16
GCST90020026_666	Hip index	9.000000e-09
GCST90020026_717	Hip index	3.000000e-10

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007817	sleep apnea measurement
EFO:0004509	hemoglobin measurement
EFO:0009188	Red cell distribution width
EFO:0004587	lymphocyte count
EFO:0004980	appendicular lean mass
EFO:0005091	monocyte count
EFO:0007985	platelet crit
EFO:0004305	erythrocyte count
EFO:0007986	reticulocyte count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

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

93 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, increases expression	7
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Aflatoxin B1	increases expression, increases methylation	3
bisphenol A	decreases expression	2
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Arsenic	increases abundance, affects expression, affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cadmium Chloride	increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
methylselenic acid	increases expression	1
potassium perchlorate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	decreases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	increases expression	1
tobacco tar	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
didecyldimethylammonium	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1KQ	Abcam HeLa ATP2B4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer