ATP2C1

Summary

ATP2C1 (ATPase secretory pathway Ca2+ transporting 1, HGNC:13211) is a protein-coding gene on chromosome 3q22.1, encoding Calcium-transporting ATPase type 2C member 1 (P98194). ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway.

The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium ions. Defects in this gene cause Hailey-Hailey disease, an autosomal dominant disorder. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 27032 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hailey-Hailey disease (Definitive, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 325 total — 42 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• MANE Select transcript: NM_001378687

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13211
Approved symbol	ATP2C1
Name	ATPase secretory pathway Ca2+ transporting 1
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1347, ATP2C1A, PMR1, SPCA1
Ensembl gene	ENSG00000017260
Ensembl biotype	protein_coding
OMIM	604384
Entrez	27032

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 36 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000328560, ENST00000359644, ENST00000422190, ENST00000428331, ENST00000504381, ENST00000504571, ENST00000504612, ENST00000504948, ENST00000505072, ENST00000505330, ENST00000507194, ENST00000507488, ENST00000508297, ENST00000508532, ENST00000508660, ENST00000509150, ENST00000509662, ENST00000510168, ENST00000510774, ENST00000513636, ENST00000513801, ENST00000514654, ENST00000515854, ENST00000533801, ENST00000868511, ENST00000868512, ENST00000939827, ENST00000939828, ENST00000939829, ENST00000939830, ENST00000939831, ENST00000939832, ENST00000939833, ENST00000939834, ENST00000950716, ENST00000950717, ENST00000950718, ENST00000950719, ENST00000950720, ENST00000950721, ENST00000950722, ENST00000950723

RefSeq mRNA: 16 — MANE Select: NM_001378687 NM_001001485, NM_001001486, NM_001001487, NM_001199179, NM_001199180, NM_001199181, NM_001199182, NM_001199183, NM_001199184, NM_001199185, NM_001378511, NM_001378512, NM_001378513, NM_001378514, NM_001378687, NM_014382

CCDS: CCDS33856, CCDS46912, CCDS46913, CCDS46914, CCDS56278, CCDS56279, CCDS56280, CCDS56281, CCDS75006

Canonical transcript exons

ENST00000510168 — 28 exons

Exon	Start	End
ENSE00000778141	130959275	130959341
ENSE00000778144	130953821	130953976
ENSE00000778145	130941591	130941699
ENSE00000778146	130940630	130940691
ENSE00000778147	130934622	130934711
ENSE00000778148	130932022	130932138
ENSE00001018047	130937428	130937463
ENSE00001151736	130963971	130964095
ENSE00001344630	130894590	130894775
ENSE00002053444	130894084	130894337
ENSE00003472829	130996680	130996796
ENSE00003500643	130980582	130980679
ENSE00003518152	130955012	130955080
ENSE00003521961	130964948	130965045
ENSE00003523924	130999518	130999659
ENSE00003526574	131001220	131003150
ENSE00003538891	130998294	130998389
ENSE00003544124	130992951	130993001
ENSE00003567458	130993932	130994098
ENSE00003570096	130930416	130930526
ENSE00003580067	130967330	130967419
ENSE00003590440	130967145	130967240
ENSE00003625873	130996043	130996111
ENSE00003633293	130969292	130969396
ENSE00003635154	130975332	130975488
ENSE00003651280	130997606	130997753
ENSE00003671306	130956104	130956179
ENSE00003681977	130979249	130979419

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.7845 / max 506.7553, expressed in 1824 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38597	18.4095	1795
38594	10.9613	1774
38593	9.5045	1741
38589	3.7952	623
38592	2.3518	424
38598	2.0919	909
38591	1.3952	374
38596	1.1949	822
38595	0.6586	439
38590	0.5497	241

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	97.77	gold quality
secondary oocyte	CL:0000655	97.68	gold quality
ventricular zone	UBERON:0003053	97.46	gold quality
stromal cell of endometrium	CL:0002255	96.95	gold quality
endothelial cell	CL:0000115	96.61	gold quality
colonic epithelium	UBERON:0000397	96.60	gold quality
islet of Langerhans	UBERON:0000006	96.53	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.38	gold quality
ganglionic eminence	UBERON:0004023	96.33	gold quality
choroid plexus epithelium	UBERON:0003911	96.04	gold quality
calcaneal tendon	UBERON:0003701	95.51	gold quality
skin of abdomen	UBERON:0001416	95.46	gold quality
rectum	UBERON:0001052	95.24	gold quality
prefrontal cortex	UBERON:0000451	95.17	gold quality
right lung	UBERON:0002167	95.13	gold quality
skin of leg	UBERON:0001511	94.91	gold quality
spinal cord	UBERON:0002240	94.91	gold quality
upper lobe of left lung	UBERON:0008952	94.87	gold quality
adenohypophysis	UBERON:0002196	94.76	gold quality
prostate gland	UBERON:0002367	94.73	gold quality
upper lobe of lung	UBERON:0008948	94.73	gold quality
pituitary gland	UBERON:0000007	94.71	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.67	gold quality
right frontal lobe	UBERON:0002810	94.47	gold quality
pigmented layer of retina	UBERON:0001782	94.44	gold quality
right uterine tube	UBERON:0001302	94.27	gold quality
oocyte	CL:0000023	94.24	gold quality
minor salivary gland	UBERON:0001830	94.17	gold quality
tibial nerve	UBERON:0001323	93.95	gold quality
zone of skin	UBERON:0000014	93.87	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	18519.76
E-CURD-119	no	2752.45
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NRG1, SP1, YY1

miRNA regulators (miRDB)

75 targeting ATP2C1, 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-4531	99.99	69.70	3181
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-335-3P	99.93	73.36	4958

Literature-anchored findings (GeneRIF, showing 40)

• failed to yield any clear correlation between the nature of the mutation and clinical features of Hailey-Hailey disease. (PMID:11841554)
• Hailey-Hailey disease (HHD) is caused by mutations in the ATP2C1 gene. (PMID:11966689)
• the crucial role of Asp-742 in the architecture of the SPCA1 ion-binding site and a role of Gly-309 in Mn2+ transport selectivity. (PMID:12707275)
• SPCA1 Ca2+ pump has a role in the Ca2+ accumulation in the Golgi apparatus of HeLa cells (PMID:12804581)
• the abnormal Ca2+ signaling seen in Hailey-Hailey disease keratinocytes correlates with decreased protein levels of ATP2C1. (PMID:14632183)
• ATP2C1 (PMR1) plays an important role, which is at least partially nonoverlapping with that of sarco(endo-)plasmic reticulum Ca(2+)-ATPases, in the control of beta-cell Ca(2+) homeostasis and insulin secretion. (PMID:14747290)
• Functional analyses of Hailey Hailey disease-mutant A528P demonstrated a low level of protein expression, despite normal levels of mRNA and correct targeting to the Golgi, suggesting instability or abnormal folding of the mutated hSPCA1 polypeptides (PMID:15191544)
• A review of the role of SPCA1 in ion homeostasis in the golgi apparatus and in Hailey-Hailey disease. (PMID:15336968)
• Two copies of mutated ATP2C1 were found in an index case diagnosed with type 2 segmental Hailey-Hailey disease. (PMID:15545997)
• important contributions of the Golgi-localized ATP2C1 protein in homeostatic maintenance throughout the secretory pathway. (PMID:15623514)
• Intracellular Ca(2+) stores and store-dependent Ca(2+) oscillations in human spermatozoa rely primarily on a thapsigargin/cyclopiazonic acid-insensitive Ca(2+) pump, SPCA1. (PMID:15811949)
• Sp1 and YY1 transactivate human ATP2C1 promoter via cis-enhancing elements and that incomplete upregulation of ATP2C1 transcription contributes to keratinocyte-specific pathogenesis of Hailey-Hailey disease. (PMID:15955096)
• Relative to SERCA1a, the active SPCA1a, SPCA1b, and SPCA1d enzymes displayed extremely high apparent affinities for cytosolic Ca(2+) in activation of the overall ATPase and phosphorylation activities. (PMID:16192278)
• The high allelic heterogeneity of the ATP2C1 gene was confirmed, which supports the notion that Hailey-Hailey disease is a genetically homogeneous disorder. (PMID:16297192)
• analysis of SPCA1 and SPCA2 isoenzymes by steady-state and transient kinetic analyses (PMID:16332677)
• a spectrum of ATP2C1 gene mutations is present in Japanese HHD patients. (PMID:16484827)
• mutations in the ATP2C1 gene may have a role in Hailey-Hailey disease (case report) (PMID:16540292)
• ATP2C1 plays a role in basal keratinocytes to stay in the undifferentiated state, and its reduction causes differentiation and up-localization to suprabasal layers most likely via manganese starvation in the Golgi apparatus of keratinocytes. (PMID:16621454)
• Mutated with a trinucleotide deletion in a case of Hailey-Hailey disease with affective disorder. (PMID:16644186)
• identifies novel nonsense and missense mutations in ATP2C1 gene in Chinese patients with Hailey-Hailey disease (PMID:17503064)
• Eight mutations were found in 8 unrelated families and 1 sporadic case, and these new findings have further improved our understanding of the role of ATP2C1 in HHD. (PMID:17911984)
• Three novel ATP2C1 mutations in Chinese patients with Hailey-Hailey disease. To date, at least 98 ATP2C1 mutations ha ve been reported worldwide in patients with HHD. (PMID:18205868)
• There is a novel deletion mutation of the ATP2C1 gene in Chinese patients with Hailey-Hailey disease. (PMID:18211433)
• Three mutations in ATP2C1 gene were found that could affect the transcription and translation, and further the function of protein encoded by ATP2C1 gene. (PMID:18247307)
• The ATP2C1 gene plays a critical role in the pathogenesis of Hailey-Hailey disease. (PMID:18259764)
• findings suggest that the novel mutation site identified in the ATP2C1 gene and local factors encountered (e.g. friction and heat) may both play important roles in the pathogenesis of Hailey-Hailey disease (PMID:18266684)
• seven different heterozygous mutations in seven of eight Hailey-Hailey disease patients (PMID:18372165)
• Two heterozygous mutations, a novel mutation p.AlaVal and a known mutation p. ARG799x, were identified. One case showed typical phenptype and the other, atypical features of keratotic papules without erosion. (PMID:18709316)
• results indicate that the novel c.2251delGT (p.V751fs) mutation in the ATP2C1 gene is responsible for Hailey-Hailey disease (HHD) in this Chinese family; this study expands the spectrum of ATP2C1 mutations associated with HHD (PMID:19126050)
• Data show that the calcium dependencies of intracellular Ca(2+)-ATPase (SERCA and SPCA) activity are the same in human Alzheimer disease and normal brain but that of plasma membrane Ca(2+)-ATPase (PMCA) is different. (PMID:19144698)
• Subsequent genetic testing revealed a deletion in the ATP2C1 gene that led us to conclude that this case of ADCF is probably a variant of familial benign chronic pemphigus (Hailey-Hailey disease). (PMID:19426624)
• The PMR1 mediated decrease in PTH mRNA levels involves the PTH mRNA 3’ Untranslated Regions, KSRP and the exosome. (PMID:19775426)
• two specific novel mutations of the ATP2CL gene were identified two typical Chinese pedigrees with Hailey-Hailey disease (PMID:20055875)
• Six novel ATP2C1 mutations are identified in Chinese patients with Hailey-Hailey disease. (PMID:20226632)
• Heterogeneous mutations of the ATP2C1 gene cause Hailey-Hailey disease in Hong Kong Chinese. (PMID:20236194)
• SPCA1 is associated with cholesterol-rich domains of HT29 cells, and the cholesterol-rich environment is essential for the functioning of the pump (PMID:20363212)
• The detection of an ATP2C1 gene mutation in this infant confirmed the diagnosis of Hailey Hailey disease (PMID:20403116)
• Correct SPCA1 functioning is crucial to intra-Golgi transport and maintenance of the Golgi ribbon. (PMID:20604898)
• SPCA1 inhibites the processing of IGF1R in MDA-MB-231 cells. (PMID:20837466)
• analysis of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn2+ efflux and protects against toxicity (PMID:21187401)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp2c1	ENSDARG00000060197
mus_musculus	Atp2c1	ENSMUSG00000032570
rattus_norvegicus	Atp2c1	ENSRNOG00000013305
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): 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), ATP2A2 (ENSG00000174437), ATP13A5 (ENSG00000187527), ATP2A1 (ENSG00000196296)

Protein

Protein identifiers

Calcium-transporting ATPase type 2C member 1 — P98194 (reviewed: P98194)

Alternative names: ATP-dependent Ca(2+) pump PMR1, Ca(2+)/Mn(2+)-ATPase 2C1, Secretory pathway Ca(2+)-transporting ATPase type 1

All UniProt accessions (10): P98194, B4E2Q0, D6R9U9, D6REJ1, D6RGE9, D6RHV9, H0Y8X9, H0Y9S7, H0Y9V7, H0YAH2

UniProt curated annotations — full annotation on UniProt →

Function. ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway. Within a catalytic cycle, acquires Ca(2+) or Mn(2+) ions on the cytoplasmic side of the membrane and delivers them to the lumenal side. The transfer of ions across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state. Plays a primary role in the maintenance of Ca(2+) homeostasis in the trans-Golgi compartment with a functional impact on Golgi and post-Golgi protein sorting as well as a structural impact on cisternae morphology. Responsible for loading the Golgi stores with Ca(2+) ions in keratinocytes, contributing to keratinocyte differentiation and epidermis integrity. Participates in Ca(2+) and Mn(2+) ions uptake into the Golgi store of hippocampal neurons and regulates protein trafficking required for neural polarity. May also play a role in the maintenance of Ca(2+) and Mn(2+) homeostasis and signaling in the cytosol while preventing cytotoxicity.

Subunit / interactions. Monomer. Homodimer.

Subcellular location. Golgi apparatus. trans-Golgi network membrane. Golgi stack membrane.

Tissue specificity. Found in most tissues except colon, thymus, spleen and leukocytes. Expressed in keratinocytes (at protein level).

Disease relevance. Hailey-Hailey disease (HHD) [MIM:169600] An autosomal dominant cutaneous disorder characterized by erythema, skin blisters and erosions, and suprabasal acantholysis. Blisters and erosions most often affect the neck, armpits, skin folds, groin and genitals. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (9)

UniProt ID	Names	Canonical?
P98194-1	1, ATP2C1A	yes
P98194-2	2, ATP2C1B, ATP2C1C
P98194-3	3, ATP2C1B
P98194-4	4, ATP2C1A
P98194-5	5, ATP2C1B
P98194-6	6
P98194-7	7
P98194-8	8
P98194-9	9, ATP2C1D

RefSeq proteins (16): NP_001001485, NP_001001486, NP_001001487, NP_001186108, NP_001186109, NP_001186110, NP_001186111, NP_001186112, NP_001186113, NP_001186114, NP_001365440, NP_001365441, NP_001365442, NP_001365443, NP_001365616, NP_055197 (=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
IPR006413	P-type_ATPase_IIA_PMR1	Family
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, 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), 2 shown:

• Ca(2+)(in) + ATP + H2O = Ca(2+)(out) + ADP + phosphate + H(+) (RHEA:18105)
• Mn(2+)(in) + ATP + H2O = Mn(2+)(out) + ADP + phosphate + H(+) (RHEA:66820)

UniProt features (158 total): helix 38, strand 37, sequence variant 23, topological domain 11, transmembrane region 10, sequence conflict 9, binding site 8, turn 7, splice variant 7, mutagenesis site 6, chain 1, active site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7YAG	ELECTRON MICROSCOPY	3.1
7YAH	ELECTRON MICROSCOPY	3.12
7YAI	ELECTRON MICROSCOPY	3.14
7YAJ	ELECTRON MICROSCOPY	3.16
8IWT	ELECTRON MICROSCOPY	3.25
7YAM	ELECTRON MICROSCOPY	3.3
8IWU	ELECTRON MICROSCOPY	3.31
8IWS	ELECTRON MICROSCOPY	3.42
8IWR	ELECTRON MICROSCOPY	3.52
8IWP	ELECTRON MICROSCOPY	3.59
8IWW	ELECTRON MICROSCOPY	3.71

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98194-F1	83.33	0.34

Antibody-complex structures (SAbDab): 4 — 7YAG, 7YAH, 7YAI, 7YAJ

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): 350 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (8): 303; 304; 306; 308; 644; 648; 738; 742

Mutagenesis-validated functional residues (6):

Position	Phenotype
39	decreases calcium-dependent autophosphorylation.
41	decreases calcium-dependent autophosphorylation and the atpase activity; when associated with a-50.
50	decreases calcium-dependent autophosphorylation and the atpase activity; when associated with a-41.
50	decreases calcium-dependent autophosphorylation.
350	impairs pump activity.
747	increases manganese transporter activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 307 (showing top): HORIUCHI_WTAP_TARGETS_DN, MODULE_169, GCM_GSPT1, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GTTAAAG_MIR302B, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_MONOATOMIC_CATION_TRANSPORT, ATGTTAA_MIR302C, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_CALCIUM_DEPENDENT_CELL_CELL_ADHESION

GO Biological Process (15): calcium ion transport (GO:0006816), manganese ion transport (GO:0006828), intracellular calcium ion homeostasis (GO:0006874), epidermis development (GO:0008544), calcium-dependent cell-cell adhesion (GO:0016339), intracellular manganese ion homeostasis (GO:0030026), actin cytoskeleton organization (GO:0030036), Golgi calcium ion homeostasis (GO:0032468), Golgi calcium ion transport (GO:0032472), positive regulation of Golgi to plasma membrane protein transport (GO:0042998), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), calcium ion transmembrane transport (GO:0070588), trans-Golgi network membrane organization (GO:0098629), monoatomic ion transport (GO:0006811), manganese ion transmembrane transport (GO:0071421)

GO Molecular Function (9): P-type calcium transporter activity (GO:0005388), calcium ion binding (GO:0005509), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), manganese ion binding (GO:0030145), metal ion binding (GO:0046872), P-type manganese transporter activity (GO:0140613), nucleotide binding (GO:0000166), transporter activity (GO:0005215)

GO Cellular Component (10): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), membrane (GO:0016020), Golgi cisterna membrane (GO:0032580), cis-Golgi network membrane (GO:0033106), cytoplasm (GO:0005737), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular monoatomic cation homeostasis	2
Golgi apparatus	2
calcium ion transport	2
monoatomic cation transmembrane transport	2
P-type ion transporter activity	2
ATPase-coupled monoatomic cation transmembrane transporter activity	2
bounding membrane of organelle	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
metal ion transport	1
transition metal ion transport	1
calcium ion homeostasis	1
tissue development	1
cell-cell adhesion	1
manganese ion homeostasis	1
cytoskeleton organization	1
actin filament-based process	1
intracellular calcium ion homeostasis	1
regulation of Golgi to plasma membrane protein transport	1
Golgi to plasma membrane protein transport	1
positive regulation of protein transport	1
positive regulation of protein localization to plasma membrane	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
membrane organization	1
transport	1
manganese ion transport	1
calcium ion transmembrane transporter activity	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
transition metal ion binding	1
cation binding	1
manganese ion transmembrane transporter activity	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP2C1	F7	P08709	895
ATP2C1	CFL1	P23528	857
ATP2C1	CFL2	Q9Y281	660
ATP2C1	PCSK9	Q8NBP7	646
ATP2C1	CCK	P06307	583
ATP2C1	TMEM165	Q9HC07	534
ATP2C1	GAPDH	P00354	480
ATP2C1	SLC30A10	Q6XR72	464
ATP2C1	ANXA5	P08758	449
ATP2C1	MMUT	P22033	445
ATP2C1	CDH1	P12830	440
ATP2C1	SLC11A2	P49281	415
ATP2C1	CASP3	P42574	414
ATP2C1	AKT1	P31749	407
ATP2C1	BCL2	P10415	406

IntAct

120 interactions, top by confidence:

A	B	Type	Score
RAD51D	RAD51B	psi-mi:“MI:0914”(association)	0.850
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
DLK1	SCAMP3	psi-mi:“MI:0914”(association)	0.530
OGFOD3	CLGN	psi-mi:“MI:0914”(association)	0.530
CYB5D2	SUN1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
OPALIN	BTAF1	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
	VAPB	psi-mi:“MI:0914”(association)	0.500
ATP2C1	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
ATP2C1	GPR35	psi-mi:“MI:0915”(physical association)	0.370
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
	SNAP23	psi-mi:“MI:0914”(association)	0.350
LMP2	WWP2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
OCRL	MYO1C	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
M	TM9SF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (152): ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Proximity Label-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), ATP2C1 (Synthetic Lethality)

ESM2 similar proteins: A3FIN4, D3K0R6, D4AA47, O14072, O23087, O43520, O60423, O75185, O94296, P22189, P23634, P39524, P54678, P57709, P90747, P98194, P98196, P98197, P98198, P98199, P98204, P98205, Q09891, Q10309, Q148W0, Q21286, Q27533, Q3TYU2, Q42883, Q4VNC0, Q4VNC1, Q5BL50, Q5XF90, Q5ZKB7, Q64542, Q6DFW5, Q6Q477, Q6UQ17, Q7XB51, Q8NB49

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

2 interactions.

A	Effect	B	Mechanism
YY1	“up-regulates quantity by expression”	ATP2C1	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	ATP2C1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 161 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
Lysosphingolipid and LPA receptors	5	38.5×	3e-05
R-HSA-425366	8	14.7×	3e-05
Class A/1 (Rhodopsin-like receptors)	9	6.7×	8e-04
SLC-mediated transmembrane transport	11	6.6×	1e-04
GPCR ligand binding	9	5.8×	2e-03
Transport of small molecules	13	3.3×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
amino acid transport	6	13.5×	2e-03
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	9.4×	8e-03
positive regulation of cytosolic calcium ion concentration	11	9.3×	3e-05
G protein-coupled receptor signaling pathway	14	3.6×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	14
Uncertain significance	131
Likely benign	17
Benign	74

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070045	NM_001378687.1(ATP2C1):c.2058-1G>A	Pathogenic
1176463	NM_001378687.1(ATP2C1):c.117+1del	Pathogenic
1183990	Single allele	Pathogenic
1264346	NM_001378687.1(ATP2C1):c.900-1G>C	Pathogenic
1299867	NM_001378687.1(ATP2C1):c.754G>T (p.Glu252Ter)	Pathogenic
1451141	NM_001378687.1(ATP2C1):c.2395C>T (p.Arg799Ter)	Pathogenic
2031331	NM_001378687.1(ATP2C1):c.2256_2259del (p.Pro753fs)	Pathogenic
2425951	NC_000003.11:g.(?130711775)(130720194_?)del	Pathogenic
2734571	NM_001378687.1(ATP2C1):c.1816C>T (p.Gln606Ter)	Pathogenic
2764746	NM_001378687.1(ATP2C1):c.1351_1354dup (p.Tyr452Ter)	Pathogenic
2765723	NM_001378687.1(ATP2C1):c.1044T>A (p.Cys348Ter)	Pathogenic
2869404	NM_001378687.1(ATP2C1):c.1309-4_1309-2delinsTTG	Pathogenic
3247013	NC_000003.11:g.(?130678099)(130686283_?)del	Pathogenic
3340302	NM_001378687.1(ATP2C1):c.423-2A>G	Pathogenic
3641488	NM_001378687.1(ATP2C1):c.727G>T (p.Glu243Ter)	Pathogenic
3657108	NM_001378687.1(ATP2C1):c.436_443del (p.Lys146fs)	Pathogenic
3657170	NM_001378687.1(ATP2C1):c.1553del (p.Gly518fs)	Pathogenic
3718604	NM_001378687.1(ATP2C1):c.2385G>A (p.Trp795Ter)	Pathogenic
3720533	NM_001378687.1(ATP2C1):c.163C>T (p.Arg55Ter)	Pathogenic
3720537	NM_001378687.1(ATP2C1):c.2416C>T (p.Arg806Ter)	Pathogenic
372308	NM_001378687.1(ATP2C1):c.2375_2378del (p.Phe792fs)	Pathogenic
373762	NM_001378687.1(ATP2C1):c.2335dup (p.Ile779fs)	Pathogenic
379537	NM_001378687.1(ATP2C1):c.2197C>T (p.Gln733Ter)	Pathogenic
3906450	NM_001378687.1(ATP2C1):c.836dup (p.Ile280fs)	Pathogenic
429384	NM_001378687.1(ATP2C1):c.1535_1536dup (p.Glu513fs)	Pathogenic
453081	NM_001378687.1(ATP2C1):c.1707del (p.Thr570fs)	Pathogenic
4686705	NM_001378687.1(ATP2C1):c.1308+1G>T	Pathogenic
4694668	NM_001378687.1(ATP2C1):c.1741+3A>G	Pathogenic
4728394	NM_001378687.1(ATP2C1):c.2321del (p.Asn774fs)	Pathogenic
4747346	NM_001378687.1(ATP2C1):c.519dup (p.Arg174fs)	Pathogenic

SpliceAI

5373 predictions. Top by Δscore:

Variant	Effect	Δscore
3:130894773:AAG:A	donor_loss	1.0000
3:130894774:AGGTA:A	donor_loss	1.0000
3:130894776:G:GC	donor_loss	1.0000
3:130894777:T:A	donor_loss	1.0000
3:130930407:A:AG	acceptor_gain	1.0000
3:130930410:TCCTA:T	acceptor_loss	1.0000
3:130930411:CCTA:C	acceptor_loss	1.0000
3:130930412:CTAG:C	acceptor_loss	1.0000
3:130930413:TAG:T	acceptor_loss	1.0000
3:130930414:A:AG	acceptor_gain	1.0000
3:130930414:AGGTT:A	acceptor_gain	1.0000
3:130930415:G:GC	acceptor_loss	1.0000
3:130930415:G:GG	acceptor_gain	1.0000
3:130930415:GGT:G	acceptor_gain	1.0000
3:130930415:GGTT:G	acceptor_gain	1.0000
3:130930415:GGTTG:G	acceptor_gain	1.0000
3:130930523:CCAA:C	donor_gain	1.0000
3:130930525:AAG:A	donor_loss	1.0000
3:130930527:G:GG	donor_gain	1.0000
3:130932010:A:AG	acceptor_gain	1.0000
3:130932011:A:G	acceptor_gain	1.0000
3:130932012:A:AG	acceptor_gain	1.0000
3:130932019:TA:T	acceptor_loss	1.0000
3:130932020:A:AG	acceptor_gain	1.0000
3:130932021:G:GG	acceptor_gain	1.0000
3:130932021:G:GT	acceptor_loss	1.0000
3:130932021:GGCT:G	acceptor_gain	1.0000
3:130932134:CTCAG:C	donor_loss	1.0000
3:130932136:CAGG:C	donor_loss	1.0000
3:130932138:GGTGA:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000004405 (3:130952788 A>T), RS1000012727 (3:130957096 T>G), RS1000025700 (3:131007846 A>G), RS1000063957 (3:130904552 A>G), RS1000066208 (3:130949965 G>A), RS1000076730 (3:130970913 G>C), RS1000102117 (3:130953127 A>T), RS1000104033 (3:130911120 T>C), RS1000113694 (3:130877584 A>G), RS1000120622 (3:130917269 T>C), RS1000165383 (3:130914296 G>A,C), RS1000174473 (3:130957505 C>T), RS1000176546 (3:130920717 C>T), RS1000183873 (3:130917137 C>G), RS1000227491 (3:131004040 C>T)

Disease associations

OMIM: gene MIM:604384 | disease phenotypes: MIM:614038, MIM:169600

GenCC curated gene-disease

Disease	Classification	Inheritance
Hailey-Hailey disease	Definitive	Autosomal dominant

Mondo (3): deafness-lymphedema-leukemia syndrome (MONDO:0013540), GATA2 deficiency with susceptibility to MDS/AML (MONDO:0042982), Hailey-Hailey disease (MONDO:0008218)

Orphanet (2): Deafness-lymphedema-leukemia syndrome (Orphanet:3226), Hailey-Hailey disease (Orphanet:2841)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000962	Hyperkeratosis
HP:0010783	Erythema
HP:0100792	Acantholysis
HP:0200037	Skin vesicle
HP:0200041	Skin erosion

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005042_7	Restless legs syndrome	4.000000e-38
GCST008151_33	Waist circumference	4.000000e-06
GCST008160_78	Waist circumference	4.000000e-06
GCST010002_439	Refractive error	5.000000e-11

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016506	Pemphigus, Benign Familial	C16.320.850.700; C17.800.827.700; C17.800.865.858

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066452 (SINGLE PROTEIN)

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Arsenic	affects cotreatment, increases abundance, increases expression, affects methylation	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Copper Sulfate	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	affects cotreatment, decreases methylation	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	increases acetylation, increases expression	1
periodate-oxidized adenosine	affects expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
bisphenol S	decreases methylation	1
picoxystrobin	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation, affects methylation	1
Aerosols	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650952	Binding	Binding affinity to human ATP2C1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2SD	Abcam HEK293T ATP2C1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06651489	PHASE2	RECRUITING	Efficacy of Guselkumab in Treating Hailey Hailey Disease
NCT04844177	PHASE2	UNKNOWN	Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
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.
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT03849989	Not specified	COMPLETED	M. Hailey-Hailey: hSPCA1 Expression and Skin Structure Upon Laser Therapy
NCT05007223	Not specified	COMPLETED	Skin Microbiome Profile in Hailey-Hailey Disease
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT01905826	Not specified	RECRUITING	Natural History Study of GATA2 Deficiency and Related Disorders