ATP2A2

Summary

ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2, HGNC:812) is a protein-coding gene on chromosome 12q24.11, encoding Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (P16615). This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines).

This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of the skeletal muscle. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol into the sarcoplasmic reticulum lumen, and is involved in regulation of the contraction/relaxation cycle. Mutations in this gene cause Darier-White disease, also known as keratosis follicularis, an autosomal dominant skin disorder characterized by loss of adhesion between epidermal cells and abnormal keratinization. Other types of mutations in this gene have been associated with various forms of muscular dystrophies. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 488 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Darier disease (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 398 total — 47 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 65
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_170665

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:812
Approved symbol	ATP2A2
Name	ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Aliases	SERCA2
Ensembl gene	ENSG00000174437
Ensembl biotype	protein_coding
OMIM	108740
Entrez	488

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000308664, ENST00000313432, ENST00000377685, ENST00000539276, ENST00000547050, ENST00000547792, ENST00000548169, ENST00000549840, ENST00000550248, ENST00000550262, ENST00000552636, ENST00000553144, ENST00000910591, ENST00000910592, ENST00000943653

RefSeq mRNA: 5 — MANE Select: NM_170665 NM_001413013, NM_001413014, NM_001413015, NM_001681, NM_170665

CCDS: CCDS9143, CCDS9144

Canonical transcript exons

ENST00000539276 — 20 exons

Exon	Start	End
ENSE00002334182	110346201	110351093
ENSE00002413987	110281247	110281907
ENSE00003459651	110340659	110340994
ENSE00003496909	110327553	110328017
ENSE00003555502	110282604	110282621
ENSE00003558606	110339503	110339721
ENSE00003569162	110332597	110332685
ENSE00003570264	110282713	110282795
ENSE00003591685	110334012	110334143
ENSE00003594390	110343232	110343434
ENSE00003599150	110342228	110342448
ENSE00003603240	110322992	110323072
ENSE00003614270	110296599	110296737
ENSE00003641443	110339281	110339403
ENSE00003646771	110346001	110346118
ENSE00003647515	110344886	110344971
ENSE00003657557	110333181	110333283
ENSE00003661162	110292020	110292124
ENSE00003668307	110326390	110326475
ENSE00003678161	110345249	110345382

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 119.2837 / max 3129.8683, expressed in 1827 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127970	108.7427	1826
127971	4.0590	1617
127969	3.3393	1421
127972	1.2429	780
127983	0.6703	325
127982	0.6342	308
127981	0.2932	116
127968	0.1303	39
127967	0.0872	28
127976	0.0847	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.90	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.90	gold quality
biceps brachii	UBERON:0001507	99.87	gold quality
body of tongue	UBERON:0011876	99.86	gold quality
triceps brachii	UBERON:0001509	99.85	gold quality
gluteal muscle	UBERON:0002000	99.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.82	gold quality
diaphragm	UBERON:0001103	99.81	gold quality
right atrium auricular region	UBERON:0006631	99.70	gold quality
vena cava	UBERON:0004087	99.67	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.57	gold quality
cardiac ventricle	UBERON:0002082	99.54	gold quality
heart left ventricle	UBERON:0002084	99.53	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.52	gold quality
cardiac atrium	UBERON:0002081	99.49	gold quality
middle temporal gyrus	UBERON:0002771	99.45	gold quality
frontal pole	UBERON:0002795	99.45	gold quality
postcentral gyrus	UBERON:0002581	99.39	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.38	gold quality
heart	UBERON:0000948	99.31	gold quality
apex of heart	UBERON:0002098	99.29	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.25	gold quality
gastrocnemius	UBERON:0001388	99.24	gold quality
parietal lobe	UBERON:0001872	99.24	gold quality
vastus lateralis	UBERON:0001379	99.22	gold quality
medial globus pallidus	UBERON:0002477	99.17	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.17	gold quality
superior frontal gyrus	UBERON:0002661	99.11	gold quality
tongue	UBERON:0001723	99.10	gold quality
paraflocculus	UBERON:0005351	99.09	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10290	no	187.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, CREB1, EGR1, ESR1, GATA4, HAX1, MEF2A, PPARA, PPARG, SP1, SP3, TBX5, TFAM, ZFPM2

miRNA regulators (miRDB)

36 targeting ATP2A2, 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-5692A	100.00	74.40	6850
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-552-5P	99.93	68.56	1583
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-4772-3P	98.04	65.60	1203
HSA-MIR-3920	97.75	69.02	1168
HSA-MIR-7112-3P	97.67	68.77	948

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Evidence for calcineurin-mediated regulation of SERCA 2a activity in human myocardium (PMID:11945024)
• A new splice variant is identified that is regulated during monocytic differentiation. (PMID:12659872)
• multiple molecular mechanisms account for the plethora of pathologic states observed in Darier disease and provide evidence for the importance of SERCA2b dimerization in pump function in vivo. (PMID:12670936)
• SERCA2a and phospholamban bind to S100A1 in the human heart (PMID:12804600)
• Structure and transcriptional regulation of the SERCA2 gene. (PMID:12805933)
• SERCA2b plays a key role in the biology of the epidermis, and its defects are sufficient to cause Darier’s disease. (PMID:12925205)
• kinetic analysis of SERCA1 and SERCA2 isoforms and the effects of mutation (PMID:12975374)
• The coexistence of SERCA1 and -2, together with complex mixtures of MyHCs in most of the fibers provide the human EOMs with a unique molecular portfolio that allows a highly specific fine-tuning regimen of contraction and relaxation. (PMID:14638697)
• TRAM2, as a part of the translocon, is required for the biosynthesis of type I collagen by coupling the activity of SERCA2b with the activity of the translocon (PMID:14749390)
• distinct, heterozygous mutations (five missense, one nonsense, one deletion, and one insertion)in Darier’s disease (PMID:15186327)
• SERCA2b, a conformationally active protein with 11 membrane-spanning regions, loses function due to decreased conformational freedom in free cholesterol-ordered membranes (PMID:15215242)
• ATP2A2 mutation found in a patient with severe Darier disease. (PMID:15316170)
• combined influence of volume overload and age on atrial SERCA2a expression (PMID:15582584)
• The combination of these histological and immunoblot results is consistent with the hypothesis that diaphragm remodeling elicited by severe COPD is characterized by a fast-to-slow SERCA isoform transformation. (PMID:15718407)
• Three novel mutations in the ATP2A2 gene in Hungarian families with Darier’s disease, including a novel splice site generating intronic nucleotide change. (PMID:15927817)
• Although upregulated SERCA2a gene expression after support with a left ventricular assist device is independent of myopathic origin, normalization of myocardial force-frequency relationship is not. (PMID:16368801)
• These results demonstrate the expression of the novel SERCA2c isoform in the heart and may point to a still unrecognized role of Plasma Memebrane Ca2+ ATPases in cardiomyopathies. (PMID:16402920)
• SERCA1, 2, and 3 sensitivity to thapsigargin is dependent on a phenylalanine 256 to valine mutation (PMID:16410239)
• new variants of the ATP2A2 gene in Darier’s disease in Chinese patients (PMID:16552539)
• This phenomenon correlates with the greater increase in [Ca2+]c induced by higher concentrations of thrombin, which further confirms that SERCA and PMCA activities are regulated by [Ca2+]c (PMID:16669348)
• Reduced expression and downpregulation is found in acantholytic dermatoses. (PMID:16675202)
• Preload stimulates SERCA expression. BNP antagonizes this mechanism. Inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. (PMID:16754798)
• Darier disease mutations in SERCA2b cause severe disruption of Ca2+ homeostasis by the defects in protein expression (PMID:16766529)
• These findings put forward a novel consequence of compromised SERCA2 function in DD wherein up-regulation of TRPC1 augments cell proliferation and restrict apoptosis. (PMID:16899508)
• ATP2A2 mutation found in a patient with severe Darier disease. (PMID:16958257)
• SERCA 2b is a protagonist in prolactin-induced proliferation of prostate cells (PMID:16965263)
• found abnormal expression of both PMCA and SERCA-type CA2+-ATPases in platelets of patients with adolescent idiopathic scoliosis (PMID:16973504)
• These results indicate that the protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation induced by KCl and that GSK3 activity regulates SERCA2 levels. (PMID:16987514)
• Phospholamban in the human esophagus might be of less importance for regulation of SERCA than in heart. Lower expression of calsequestrin and calreticulin might contribute to increased lower esophageal sphincter pressure in achalasia. (PMID:17009399)
• Germline alterations of ATP2A2 may predispose to lung and colon cancer: an impaired ATP2A2 gene might be involved directly or indirectly as an early event in carcinogenesis. (PMID:17116488)
• In cells overexpressing SERCA2, the cyclic GMP-independent, redox regulation of SERCA2 cysteine-674 is required for the inhibition of cell migration by both exogenous and endogenously generated NO. (PMID:17234728)
• In patients with COPD, SERCA2 concentration is reduced and the protein is tyrosine-nitrated in skeletal muscle from patients with low Body Mass Index compared to those with normal BMI. (PMID:17257557)
• Either decreases in SERCA2a expression, increases in Na(+)/Ca(2+) exchanger (NCX) expression or elevated Na(+)(i) have been independently proposed as mediators of the negative FFR. (PMID:17395056)
• results suggest a protective role of the A724A (c.2171G>A) polymorphism of ATP2A2 in subjects without hypertension (PMID:17439322)
• Results describe abrupt changes in the expression of FKBP12.6, SERCA2a, PKA, and ECE on reperfusion against ischemia, which are responsible for the rapid occurrence of ventricular fibrillation, and their prevention by CPU86017. (PMID:17506935)
• Gene expression of ATP2A2 was studied in children with congenital heart defects. (PMID:17515962)
• Histidine-rich Ca-binding protein may play a key role in the regulation of SR Ca cycling through its direct interactions with SERCA2 and triadin, mediating a fine cross talk between SR Ca uptake and release in the heart. (PMID:17526652)
• The sarco(endo)plasmic reticulum Ca(2+) ATPase 2b (SERCA2b), which maintains high Ca(2+) concentration in the lumen of the endoplasmic reticulum, interacts specifically with the human delta opioid receptor. (PMID:17588601)
• Sp1 plays an important and positive role in ATP2A2 gene expression in normal human keratinocytes in vivo and in vitro. (PMID:17597815)
• The Japanese pedigree presented here has the same mutation, p.N767S, as three previously reported unrelated European families, establishing it as a common mutation in HDD. (PMID:17635506)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp2a2b	ENSDARG00000005122
mus_musculus	Atp2a2	ENSMUSG00000029467
rattus_norvegicus	Atp2a2	ENSRNOG00000001285
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), ATP12A (ENSG00000075673), ATP1A3 (ENSG00000105409), ATP4A (ENSG00000105675), ATP13A1 (ENSG00000105726), ATP7B (ENSG00000123191), ATP13A4 (ENSG00000127249), ATP1A4 (ENSG00000132681), ATP13A3 (ENSG00000133657), ATP2B2 (ENSG00000157087), ATP13A2 (ENSG00000159363), ATP1A1 (ENSG00000163399), ATP7A (ENSG00000165240), ATP13A5 (ENSG00000187527), ATP2A1 (ENSG00000196296)

Protein

Protein identifiers

Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 — P16615 (reviewed: P16615)

Alternative names: Calcium pump 2, Calcium-transporting ATPase sarcoplasmic reticulum type, slow twitch skeletal muscle isoform, Endoplasmic reticulum class 1/2 Ca(2+) ATPase

All UniProt accessions (6): A0A0C4DH86, A0A0S2Z3L2, P16615, F8W1Z7, H7C5W9, J3QSY6

UniProt curated annotations — full annotation on UniProt →

Function. This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Involved in autophagy in response to starvation. Upon interaction with VMP1 and activation, controls ER-isolation membrane contacts for autophagosome formation. Also modulates ER contacts with lipid droplets, mitochondria and endosomes. In coordination with FLVCR2 mediates heme-stimulated switching from mitochondrial ATP synthesis to thermogenesis. Involved in the regulation of the contraction/relaxation cycle. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca(2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca(2+) signaling cascades that promote osteoclast differentiation and activation.

Subunit / interactions. Interacts with sarcolipin (SLN); the interaction inhibits ATP2A2 Ca(2+) affinity. Interacts with phospholamban (PLN); the interaction inhibits ATP2A2 Ca(2+) affinity. Interacts with myoregulin (MRLN). Interacts with ARLN and ERLN; the interactions inhibit ATP2A2 Ca(2+) affinity. Interacts with STRIT1/DWORF; the interaction results in activation of ATP2A2. Interacts with the monomeric forms of SLN, PLN, ARLN, ERLN and STRI1/DWORF. Interacts with HAX1. Interacts with S100A8 and S100A9. Interacts with SLC35G1 and STIM1. Interacts with TMEM203. Interacts with TMEM64 and PDIA3. Interacts with TMX1. Interacts with TMX2. Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2. Interacts with ULK1. Interacts with S100A1 in a Ca(2+)-dependent manner. Interacts with TUNAR. Interacts with FLVCR2; this interaction occurs in the absence of heme and promotes ATP2A2 proteasomal degradation; this complex is dissociated upon heme binding. Interacts with FNIP1. Interacts with TRAM2 (via C-terminus).

Subcellular location. Endoplasmic reticulum membrane. Sarcoplasmic reticulum membrane.

Tissue specificity. Isoform 1 is widely expressed in smooth muscle and nonmuscle tissues such as in adult skin epidermis, with highest expression in liver, pancreas and lung, and intermediate expression in brain, kidney and placenta. Also expressed at lower levels in heart and skeletal muscle. Isoforms 2 and 3 are highly expressed in the heart and slow twitch skeletal muscle. Expression of isoform 3 is predominantly restricted to cardiomyocytes and in close proximity to the sarcolemma. Both isoforms are mildly expressed in lung, kidney, liver, pancreas and placenta. Expression of isoform 3 is amplified during monocytic differentiation and also observed in the fetal heart.

Post-translational modifications. Nitrated under oxidative stress. Nitration on the two tyrosine residues inhibits catalytic activity. Serotonylated on Gln residues by TGM2 in response to hypoxia, leading to its inactivation.

Disease relevance. Acrokeratosis verruciformis (AKV) [MIM:101900] A localized disorder of keratinization, which is inherited as an autosomal dominant trait. Its onset is early in life with multiple flat-topped, flesh-colored papules on the hands and feet, punctate keratoses on the palms and soles, with varying degrees of nail involvement. The histopathology shows a distinctive pattern of epidermal features with hyperkeratosis, hypergranulosis and acanthosis together with papillomatosis. These changes are frequently associated with circumscribed elevations of the epidermis that are said to resemble church spires. There are no features of dyskeratosis or acantholysis, the typical findings in lesions of Darier disease. The disease is caused by variants affecting the gene represented in this entry. Darier disease (DD) [MIM:124200] A skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp and forehead), palmoplantar pits and distinctive nail abnormalities. It is due to loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Patients with mild disease may have no more than a few scattered keratotic papules or subtle nail changes, whereas those with severe disease are handicapped by widespread malodorous keratotic plaques. Some patients present with hemorrhage into acantholytic vesicles on the palms and dorsal aspects of the fingers which gives rise to black macules. In a few families affected by Darier disease, neuropsychiatric abnormalities such as mild intellectual disability, schizophrenia, bipolar disorder and epilepsy have been reported. Stress, UV exposure, heat, sweat, friction and oral contraception exacerbate disease symptoms. Clinical variants of Darier disease include hypertrophic, vesicobullous, hypopigmented, cornifying, zosteriform or linear, acute and comedonal subtypes. Comedonal Darier disease is characterized by the coexistence of acne-like comedonal lesions with typical Darier hyperkeratotic papules on light-exposed areas. At histopathologic level, comedonal Darier disease differs from classic Darier disease in the prominent follicular involvement and the presence of greatly elongated dermal villi. The disease is caused by variants affecting the gene represented in this entry. Rhabdomyolysis 2 (RHABDO2) [MIM:621236] An autosomal dominant disorder characterized by recurrent rhabdomyolysis, triggered predominantly by fever or infection. Rhabdomyolysis is the rapid breakdown of damaged or injured skeletal myofibres and may require intensive care management. Muscle breakdown results in release of myofibrillar content into the extracellular space and circulation, resulting in hyperCKemia (hyperCK) and myoglobinuria. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Has different conformational states with differential Ca2+ affinity. The E1 conformational state (active form) shows high Ca(2+) affinity, while the E2 state exhibits low Ca(2+) affinity. Binding of ATP allosterically increases its affinity for subsequent binding of Ca2+. Reversibly inhibited by phospholamban (PLN) at low calcium concentrations. PLN inhibits ATP2A2 Ca(2+) affinity by disrupting its allosteric activation by ATP. Inhibited by sarcolipin (SLN) and myoregulin (MRLN). The inhibition is blocked by VMP1. Enhanced by STRIT1/DWORF; STRIT1 increases activity by displacing sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN). Stabilizes SERCA2 in its E2 state.

Domain organisation. Ca(2+) and ATP binding cause major rearrangements of the cytoplasmic and transmembrane domains. According to the E1-E2 model, Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp, giving rise to E1P. A conformational change of the phosphoenzyme gives rise to the low-affinity E2P state that exposes the Ca(2+) ions to the lumenal side and promotes Ca(2+) release. Dephosphorylation of the active site Asp mediates the subsequent return to the E1 conformation. PLN and SLN both have a single transmembrane helix; both occupy a similar binding site that is situated between the ATP2A2 transmembrane helices.

Miscellaneous. Ubiquitous housekeeping isoform. Cardiac/slow twitch, muscle specific isoform. Has a lower affinity for calcium and a higher catalytic turnover rate. May be due to intron retention. Shows a lower apparent affinity for cytosolic calcium than isoform 2 and a catalytic turnover rate similar to isoform 1.

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

Isoforms (5)

UniProt ID	Names	Canonical?
P16615-1	1, ATP2A2B, Class 2-4, HK1, SERCA2b	yes
P16615-2	2, ATP2A2A, Class 1, HK2, SERCA2a
P16615-3	3, SERCA2C
P16615-4	4
P16615-5	5

RefSeq proteins (5): NP_001399942, NP_001399943, NP_001399944, NP_001672, NP_733765* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001757	P_typ_ATPase	Family
IPR004014	ATPase_P-typ_cation-transptr_N	Domain
IPR005782	P-type_ATPase_IIA	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
IPR059000	ATPase_P-type_domA	Domain

Pfam: PF00122, PF00689, PF00690, PF08282, PF13246

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (219 total): sequence variant 49, helix 49, strand 43, binding site 25, turn 13, topological domain 11, transmembrane region 10, modified residue 7, region of interest 4, splice variant 4, chain 1, mutagenesis site 1, active site 1, disulfide bond 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
6LLY	ELECTRON MICROSCOPY	2.8
6LN5	ELECTRON MICROSCOPY	2.8
6LN7	ELECTRON MICROSCOPY	2.8
6LLE	ELECTRON MICROSCOPY	2.9
6LN6	ELECTRON MICROSCOPY	2.9
7W7U	ELECTRON MICROSCOPY	3
7W7V	ELECTRON MICROSCOPY	3
7BT2	X-RAY DIFFRACTION	3
6LN8	ELECTRON MICROSCOPY	3.1
6JJU	X-RAY DIFFRACTION	3.2
7W7W	ELECTRON MICROSCOPY	3.2
7E7S	ELECTRON MICROSCOPY	3.3
6LN9	ELECTRON MICROSCOPY	3.4
7W7T	ELECTRON MICROSCOPY	3.4
5ZTF	X-RAY DIFFRACTION	3.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16615-F1	85.46	0.45

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): 351 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (25): 304; 305; 307; 309; 351; 353; 353; 442; 489; 514; 559; 624 …

Post-translational modifications (7): 38, 294, 295, 441, 531, 580, 663

Disulfide bonds (1): 875–887

Mutagenesis-validated functional residues (1):

Position	Phenotype
256	no effect on interaction with vmp1.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1912420	Pre-NOTCH Processing in Golgi
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-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1912422	Pre-NOTCH Expression and Processing
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: 636 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, REACTOME_SIGNALING_BY_NOTCH, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, MODY_HIPPOCAMPUS_POSTNATAL, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_VACUOLE_ORGANIZATION, GOBP_SKELETAL_MUSCLE_ADAPTATION, GCANCTGNY_MYOD_Q6, TTTGTAG_MIR520D, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, CGGAARNGGCNG_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_REGULATION_OF_EXOCYTOSIS

GO Biological Process (36): autophagosome assembly (GO:0000045), regulation of the force of heart contraction (GO:0002026), intracellular calcium ion homeostasis (GO:0006874), ER-nucleus signaling pathway (GO:0006984), cell adhesion (GO:0007155), epidermis development (GO:0008544), positive regulation of heart rate (GO:0010460), positive regulation of cardiac muscle cell apoptotic process (GO:0010666), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), transition between fast and slow fiber (GO:0014883), cardiac muscle hypertrophy in response to stress (GO:0014898), autophagosome membrane docking (GO:0016240), endoplasmic reticulum calcium ion homeostasis (GO:0032469), positive regulation of endoplasmic reticulum calcium ion concentration (GO:0032470), T-tubule organization (GO:0033292), monoatomic ion transmembrane transport (GO:0034220), cellular response to oxidative stress (GO:0034599), response to endoplasmic reticulum stress (GO:0034976), negative regulation of heart contraction (GO:0045822), relaxation of cardiac muscle (GO:0055119), neuron cellular homeostasis (GO:0070050), sarcoplasmic reticulum calcium ion transport (GO:0070296), calcium ion transmembrane transport (GO:0070588), regulation of cardiac muscle cell membrane potential (GO:0086036), regulation of cardiac muscle cell action potential involved in regulation of contraction (GO:0098909), organelle localization by membrane tethering (GO:0140056), regulation of calcium ion-dependent exocytosis of neurotransmitter (GO:1903233), calcium ion transport from cytosol to endoplasmic reticulum (GO:1903515), regulation of cardiac conduction (GO:1903779), calcium ion import into sarcoplasmic reticulum (GO:1990036), obsolete mitochondrion-endoplasmic reticulum membrane tethering (GO:1990456), muscle system process (GO:0003012), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), regulation of muscle contraction (GO:0006937), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059)

GO Molecular Function (14): calcium channel regulator activity (GO:0005246), P-type calcium transporter activity (GO:0005388), calcium ion binding (GO:0005509), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), transmembrane transporter binding (GO:0044325), S100 protein binding (GO:0044548), P-type calcium transporter activity involved in regulation of cardiac muscle cell membrane potential (GO:0086039), lncRNA binding (GO:0106222), nucleotide binding (GO:0000166), transporter activity (GO:0005215), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), longitudinal sarcoplasmic reticulum (GO:0014801), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), platelet dense tubular network membrane (GO:0031095), sarcoplasmic reticulum membrane (GO:0033017), calcium ion-transporting ATPase complex (GO:0090534), ribbon synapse (GO:0097470)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Pre-NOTCH Expression and Processing	1
Platelet calcium homeostasis	1
Cardiac conduction	1
Ion channel transport	1
Signal Transduction	1
Signaling by NOTCH	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
protein binding	3
regulation of heart contraction	2
endoplasmic reticulum	2
sarcoplasmic reticulum	2
cellular anatomical structure	2
bounding membrane of organelle	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
regulation of biological quality	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
intracellular signal transduction	1
cellular process	1
tissue development	1
regulation of heart rate	1
positive regulation of heart contraction	1
cardiac muscle cell apoptotic process	1
positive regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
calcium-mediated signaling	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
regulation of skeletal muscle adaptation	1
muscle hypertrophy in response to stress	1
cardiac muscle hypertrophy	1
cardiac muscle adaptation	1
autophagosome maturation	1
organelle localization by membrane tethering	1
intracellular calcium ion homeostasis	1
endoplasmic reticulum calcium ion homeostasis	1
plasma membrane organization	1
muscle cell development	1
membrane organization	1
monoatomic ion transport	1
transmembrane transport	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

272 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
	XPO1	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
WFS1	ATP2A2	psi-mi:“MI:0915”(physical association)	0.520
ATP2A2	F2RL1	psi-mi:“MI:0915”(physical association)	0.510
	SCD	psi-mi:“MI:0914”(association)	0.500
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
TPTE	NOP56	psi-mi:“MI:2364”(proximity)	0.420
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
NSA2	ATP2A2	psi-mi:“MI:0915”(physical association)	0.400
MPTX1	ATP2A2	psi-mi:“MI:0915”(physical association)	0.400
SLC4A4	ATP2A2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (535): ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A2 (Affinity Capture-RNA), ATP2A2 (Co-fractionation), ATP2A2 (Co-fractionation), ATP2A2 (Co-fractionation), ATP2A2 (Co-fractionation), ATP2A2 (Co-fractionation), NDUFS4 (Co-fractionation)

ESM2 similar proteins: O14983, O22218, O23087, O46674, O55143, O77696, O81108, P04191, P07038, P09626, P11507, P11607, P13585, P16615, P18596, P19156, P20647, P20648, P22700, P27112, P35315, P35316, P50996, P54209, P70083, P92939, Q00779, Q03669, Q0VCY0, Q292Q0, Q2QY12, Q2RAS0, Q42883, Q4WND5, Q64436, Q64518, Q64578, Q7PPA5, Q8R429, Q8RUN1

Diamond homologs: A0A143ZZK9, A2VDL6, A7L9Z8, B9QMJ0, D2WKD8, O13397, O13398, O14983, O23087, O34431, O46674, O55143, O75185, O77696, P04074, P04191, P05023, P06685, P07038, P09572, P09626, P09627, P11507, P11607, P11718, P12522, P13585, P13586, P16615, P17326, P18596, P18907, P19156, P20431, P20647, P20648, P22189, P22700, P25489, P27112

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
CAMK2A	“up-regulates activity”	ATP2A2	phosphorylation
HAX1	“down-regulates quantity by repression”	ATP2A2	“transcriptional regulation”
ATP2A2	“up-regulates quantity”	calcium(2+)	relocalization
PDE3A	“down-regulates activity”	ATP2A2	binding
HAX1	“down-regulates quantity by destabilization”	ATP2A2	binding
GSK3B	“down-regulates activity”	ATP2A2	phosphorylation
MAPK9	“up-regulates activity”	ATP2A2	phosphorylation
PLN	“down-regulates activity”	ATP2A2	binding
HRC	“down-regulates activity”	ATP2A2	binding
thapsigargin	“down-regulates activity”	ATP2A2	“chemical inhibition”
SLN	“down-regulates activity”	ATP2A2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 200 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
Defective CFTR causes cystic fibrosis	7	12.1×	1e-03
MAPK6/MAPK4 signaling	8	8.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
tumor necrosis factor-mediated signaling pathway	6	12.3×	4e-03
learning or memory	7	10.5×	4e-03
protein dephosphorylation	7	9.6×	4e-03
positive regulation of canonical NF-kappaB signal transduction	12	5.4×	4e-03
positive regulation of apoptotic process	12	4.2×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	46
Uncertain significance	159
Likely benign	61
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071045	NM_170665.4(ATP2A2):c.348del (p.Ile116fs)	Pathogenic
1073748	NC_000012.11:g.(?110719595)(110720600_?)del	Pathogenic
1323820	NM_170665.4(ATP2A2):c.2560del (p.Trp854fs)	Pathogenic
1693414	NM_170665.4(ATP2A2):c.1A>G (p.Met1Val)	Pathogenic
17789	NM_170665.4(ATP2A2):c.68G>A (p.Gly23Glu)	Pathogenic
17790	NM_170665.4(ATP2A2):c.322C>T (p.Gln108Ter)	Pathogenic
17793	NM_170665.4(ATP2A2):c.803G>T (p.Cys268Phe)	Pathogenic
17794	NM_170665.4(ATP2A2):c.1678T>C (p.Cys560Arg)	Pathogenic
17795	NM_170665.4(ATP2A2):c.137-13_137-12insNNNNNNNNNNNNNNNNNN	Pathogenic
17796	NM_170665.4(ATP2A2):c.2258ACA[2] (p.Asn755del)	Pathogenic
17797	NM_170665.4(ATP2A2):c.2682C>A (p.Tyr894Ter)	Pathogenic
17798	NM_170665.4(ATP2A2):c.2305G>A (p.Gly769Arg)	Pathogenic
17799	NM_170665.4(ATP2A2):c.1805C>T (p.Pro602Leu)	Pathogenic
17800	NM_170665.4(ATP2A2):c.392G>A (p.Arg131Gln)	Pathogenic
2130898	NM_170665.4(ATP2A2):c.2939A>T (p.Asp980Val)	Pathogenic
2137436	NM_170665.4(ATP2A2):c.2407G>A (p.Ala803Thr)	Pathogenic
2424212	NC_000012.11:g.(?110729805)(110729949_?)del	Pathogenic
2424213	NC_000012.11:g.(?110646956)(110765842_?)del	Pathogenic
2507396	NM_170665.4(ATP2A2):c.1013C>T (p.Ser338Phe)	Pathogenic
2582907	NM_170665.4(ATP2A2):c.632G>A (p.Gly211Asp)	Pathogenic
2705845	NM_170665.4(ATP2A2):c.428_429del (p.Lys143fs)	Pathogenic
2735966	NC_000012.12:g.110282602AG[1]	Pathogenic
2735967	NM_170665.4(ATP2A2):c.479C>T (p.Pro160Leu)	Pathogenic
2735974	NM_170665.4(ATP2A2):c.2104G>A (p.Asp702Asn)	Pathogenic
280355	NM_170665.4(ATP2A2):c.2058del (p.Ile686fs)	Pathogenic
280505	NM_170665.4(ATP2A2):c.1A>T (p.Met1Leu)	Pathogenic
280566	NM_170665.4(ATP2A2):c.291_292del (p.Leu98fs)	Pathogenic
2813682	NM_170665.4(ATP2A2):c.1645C>T (p.Arg549Ter)	Pathogenic
2823827	NM_170665.4(ATP2A2):c.1653G>A (p.Trp551Ter)	Pathogenic
2831942	NM_170665.4(ATP2A2):c.1348del (p.Glu450fs)	Pathogenic

SpliceAI

3233 predictions. Top by Δscore:

Variant	Effect	Δscore
12:110281890:A:T	donor_gain	1.0000
12:110281904:AACG:A	donor_loss	1.0000
12:110281908:G:GG	donor_gain	1.0000
12:110281908:G:T	donor_loss	1.0000
12:110282558:A:AG	acceptor_gain	1.0000
12:110282559:A:G	acceptor_gain	1.0000
12:110282560:C:G	acceptor_gain	1.0000
12:110282707:TTACA:T	acceptor_loss	1.0000
12:110282708:TACAG:T	acceptor_loss	1.0000
12:110282709:ACAGG:A	acceptor_loss	1.0000
12:110282710:CAGGA:C	acceptor_loss	1.0000
12:110282711:A:AG	acceptor_gain	1.0000
12:110282711:AGG:A	acceptor_loss	1.0000
12:110282712:G:C	acceptor_loss	1.0000
12:110282712:G:GG	acceptor_gain	1.0000
12:110282712:GGA:G	acceptor_gain	1.0000
12:110282712:GGAAA:G	acceptor_gain	1.0000
12:110282791:CTTTT:C	donor_gain	1.0000
12:110282792:TTTT:T	donor_gain	1.0000
12:110282793:TTT:T	donor_gain	1.0000
12:110282793:TTTGT:T	donor_loss	1.0000
12:110282794:TT:T	donor_gain	1.0000
12:110282795:TG:T	donor_loss	1.0000
12:110282796:G:GG	donor_gain	1.0000
12:110282796:GT:G	donor_loss	1.0000
12:110282797:T:TC	donor_loss	1.0000
12:110282798:AA:A	donor_loss	1.0000
12:110296593:A:AG	acceptor_gain	1.0000
12:110296594:T:G	acceptor_gain	1.0000
12:110296594:TACAG:T	acceptor_gain	1.0000

AlphaMissense

6844 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:110281857:G:A	G23E	1.000
12:110282770:T:C	L65S	1.000
12:110292072:C:G	P91R	1.000
12:110292081:T:A	I94N	1.000
12:110292090:T:A	I97K	1.000
12:110292090:T:G	I97R	1.000
12:110292103:T:A	N101K	1.000
12:110292103:T:G	N101K	1.000
12:110292104:G:C	A102P	1.000
12:110296608:G:C	A112P	1.000
12:110296617:G:C	A115P	1.000
12:110296626:G:C	A118P	1.000
12:110296630:T:A	L119H	1.000
12:110296630:T:C	L119P	1.000
12:110296666:G:C	R131P	1.000
12:110322995:G:A	G156D	1.000
12:110323004:T:A	V159D	1.000
12:110323067:T:C	L180P	1.000
12:110323072:G:C	G182R	1.000
12:110323072:G:T	G182C	1.000
12:110326390:G:A	G182D	1.000
12:110326390:G:T	G182V	1.000
12:110326412:G:C	K189N	1.000
12:110326412:G:T	K189N	1.000
12:110326463:C:A	N206K	1.000
12:110326463:C:G	N206K	1.000
12:110327571:G:A	G217R	1.000
12:110327571:G:C	G217R	1.000
12:110327571:G:T	G217W	1.000
12:110327572:G:A	G217E	1.000

dbSNP variants (sampled 300 via entrez): RS1000095277 (12:110290884 T>G), RS1000109161 (12:110282054 G>A,T), RS1000180498 (12:110323845 G>A), RS1000201844 (12:110347433 A>G), RS1000232860 (12:110324043 T>C), RS1000363757 (12:110335212 G>A), RS1000375993 (12:110328771 G>A), RS1000458771 (12:110334928 C>G,T), RS1000459432 (12:110286328 T>C,G), RS1000473460 (12:110311885 T>A), RS1000516196 (12:110324827 T>A), RS1000540052 (12:110286643 T>A,G), RS1000567102 (12:110325133 G>C), RS1000592023 (12:110341654 C>T), RS1000611115 (12:110299104 G>A,C)

Disease associations

OMIM: gene MIM:108740 | disease phenotypes: MIM:101900, MIM:124200, MIM:621236

GenCC curated gene-disease

Disease	Classification	Inheritance
Darier disease	Definitive	Autosomal dominant
acrokeratosis verruciformis	Definitive	Autosomal dominant

Mondo (3): acrokeratosis verruciformis (MONDO:0007048), Darier disease (MONDO:0007417), rhabdomyolysis, susceptibility to, 2 (MONDO:0980721)

Orphanet (2): Darier disease (Orphanet:218), Acrokeratosis verruciformis of Hopf (Orphanet:79151)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000498	Blepharitis
HP:0000716	Depression
HP:0000962	Hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001000	Abnormality of skin pigmentation
HP:0001034	Hypermelanotic macule
HP:0001036	Parakeratosis
HP:0001072	Thickened skin
HP:0001097	Keratoconjunctivitis sicca
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001595	Abnormal hair morphology
HP:0001597	Abnormal nail morphology
HP:0001798	Anonychia
HP:0001807	Ridged nail
HP:0001808	Fragile nails
HP:0001820	Leukonychia
HP:0001919	Acute kidney injury
HP:0002460	Distal muscle weakness
HP:0002913	Myoglobinuria
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003326	Myalgia
HP:0003558	Viral infection-induced rhabdomyolysis
HP:0003577	Congenital onset
HP:0003584	Late onset
HP:0003596	Middle age onset

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000189_3	Protein quantitative trait loci	1.000000e-07
GCST002500_71	QT interval	3.000000e-12
GCST002539_18	Schizophrenia	1.000000e-09
GCST002726_42	Glucose homeostasis traits	7.000000e-06
GCST004946_44	Schizophrenia	3.000000e-09
GCST006803_14	Schizophrenia	3.000000e-14
GCST007201_177	Schizophrenia	3.000000e-10
GCST007201_209	Schizophrenia	6.000000e-10
GCST008151_34	Waist circumference	4.000000e-06
GCST008160_79	Waist circumference	4.000000e-06
GCST008595_122	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	2.000000e-08
GCST009600_34	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	5.000000e-08
GCST010919_13	QT interval	4.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004813	alpha globulin measurement
EFO:0004682	QT interval
EFO:0006831	acute insulin response measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007644	Darier Disease	C16.320.850.190; C17.800.428.275; C17.800.827.190

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3831290 (PROTEIN FAMILY), CHEMBL3901 (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: 93,882 (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
CHEMBL140	CURCUMIN	3	93,882

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1860561	ATP2A2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — P2A P-type ATPases: Ca²⁺-ATPases

ChEMBL bioactivities

13 potent at pChembl≥5 of 14 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.89	Ki	1.3	nM	CHEMBL4514624
7.96	Ki	11	nM	CHEMBL4207081
7.80	EC50	16	nM	CHEMBL5435124
7.63	Kd	23.16	nM	CHEMBL5653589
7.63	ED50	23.16	nM	CHEMBL5653589
7.57	Ki	27	nM	CHEMBL4216774
7.05	IC50	90	nM	CHEMBL468766
6.68	IC50	210	nM	CHEMBL4534285
5.70	IC50	2000	nM	CHEMBL480626
5.30	IC50	5000	nM	PAXILLINE
5.16	IC50	7000	nM	CURCUMIN
5.01	Kd	9667	nM	CHEMBL3752910
5.01	ED50	9667	nM	CHEMBL3752910

PubChem BioAssay actives

11 with measured affinity, of 67 total; 11 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
(1R,2S,6S,7E,10S,11E,13S,15S)-6-[(2R,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-methoxyoxan-2-yl]oxy-10-methoxy-11,13-dimethyl-2-[(1Z,4E)-2-methylhexa-1,4-dienyl]-3,16,17-trioxabicyclo[13.2.2]nonadeca-7,11,18-trien-4-one	1605049: Inhibition of SERCA2a (unknown origin)	ki	0.0013	uM
(4S,5E,8S,9E,11S,13E,15E,18R)-4-[(2R,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-methoxyoxan-2-yl]oxy-8-methoxy-9,11-dimethyl-18-[(1Z,4E)-2-methylhexa-1,4-dienyl]-1-oxacyclooctadeca-5,9,13,15-tetraen-2-one	1605049: Inhibition of SERCA2a (unknown origin)	ki	0.0110	uM
1-[4-[4-(1-hydroxycyclopropyl)butyl-[4-(7-methoxy-3,5-dihydro-2H-1,4-benzothiazepin-4-yl)butyl]amino]butyl]cyclopropan-1-ol	2023095: Activation of SERCA2a in human HEK293T cells endoplasmic reticulum assessed as increase in calcium release measured for 10 mins in presence of ATP by NADH fluorescence-coupled ATPase assay	ec50	0.0160	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147909: Binding affinity to human ATP2A2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0232	uM
(4S,5E,8S,9E,11S,13E,15E,18R)-4-hydroxy-8-methoxy-9,11-dimethyl-18-[(1Z,4E)-2-methylhexa-1,4-dienyl]-1-oxacyclooctadeca-5,9,13,15-tetraen-2-one	1605049: Inhibition of SERCA2a (unknown origin)	ki	0.0270	uM
(2R,3S,5Z,9R)-5-(1-hydroxyethylidene)-8,8-dimethyl-7,16-diazapentacyclo[9.6.1.02,9.03,7.015,18]octadeca-1(17),11(18),12,14-tetraene-4,6-dione	1605040: Inhibition of human SERCA2b expressed in COS7 cells microsomal membranes preincubated for 10 mins followed by addition of ATP and measured after 40 mins by ELISA method	ic50	0.0900	uM
[(3S,3aR,4S,6R,6aR,7S,8S,9bS)-6-acetyloxy-4-butanoyloxy-3,3a-dihydroxy-3,6,9-trimethyl-8-[(Z)-2-methylbut-2-enoyl]oxy-2-oxo-4,5,6a,7,8,9b-hexahydroazuleno[4,5-b]furan-7-yl] octanoate	1605040: Inhibition of human SERCA2b expressed in COS7 cells microsomal membranes preincubated for 10 mins followed by addition of ATP and measured after 40 mins by ELISA method	ic50	0.2100	uM
2,5-ditert-butylbenzene-1,4-diol	1605040: Inhibition of human SERCA2b expressed in COS7 cells microsomal membranes preincubated for 10 mins followed by addition of ATP and measured after 40 mins by ELISA method	ic50	2.0000	uM
(1S,2R,5S,7R,11S,14S)-11-hydroxy-7-(2-hydroxypropan-2-yl)-1,2-dimethyl-6-oxa-23-azahexacyclo[12.10.0.02,11.05,10.016,24.017,22]tetracosa-9,16(24),17,19,21-pentaen-8-one	1605059: Inhibition of SERCA2b in human platelet microsomes by enzyme-coupled method	ic50	5.0000	uM
Curcumin	1605059: Inhibition of SERCA2b in human platelet microsomes by enzyme-coupled method	ic50	7.0000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147909: Binding affinity to human ATP2A2 incubated for 45 mins by Kinobead based pull down assay	kd	9.6668	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ozone	increases expression, increases abundance, affects expression, affects response to substance, affects cotreatment (+1 more)	4
Rosiglitazone	decreases activity, increases expression	3
Valproic Acid	affects expression, increases expression, increases methylation	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	affects expression, increases expression	2
sodium arsenite	affects cotreatment, decreases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases expression, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases expression, increases abundance	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Cadmium Chloride	increases expression	2
Thapsigargin	affects response to substance, increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, affects expression, increases reaction	2
MYK-461	decreases expression, decreases reaction	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	decreases expression, increases abundance, affects cotreatment	1
methylselenic acid	increases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
tributyltin	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetramethylpyrazine	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
nickel chloride	decreases expression	1
ochratoxin A	decreases expression	1
oxymatrine	affects cotreatment, decreases expression	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118684	Binding	Binding affinity to ATP2A2 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D7KS	Ubigene A-549 ATP2A2 KO	Cancer cell line	Male
CVCL_UM38	WAe009-A-14	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02782702	PHASE1	COMPLETED	Evaluation of the Improvement of Quality of Life of Patients Suffering From Hailey Hailey or Darier Disease After Injections of Botulism Toxin Into Large Folds.
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT06614777	Not specified	RECRUITING	Characterization of the Cytokine Profile and the Microbiome in Darier’s Disease