ATP8A1

Summary

ATP8A1 (ATPase phospholipid transporting 8A1, HGNC:13531) is a protein-coding gene on chromosome 4p13, encoding Phospholipid-transporting ATPase IA (Q9Y2Q0). Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids.

The P-type adenosinetriphosphatases (P-type ATPases) are a family of proteins which use the free energy of ATP hydrolysis to drive uphill transport of ions across membranes. Several subfamilies of P-type ATPases have been identified. One subfamily catalyzes transport of heavy metal ions. Another subfamily transports non-heavy metal ions (NMHI). The protein encoded by this gene is a member of the third subfamily of P-type ATPases and acts to transport amphipaths, such as phosphatidylserine. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10396 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 136 total — 2 pathogenic
• MANE Select transcript: NM_006095

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13531
Approved symbol	ATP8A1
Name	ATPase phospholipid transporting 8A1
Location	4p13
Locus type	gene with protein product
Status	Approved
Aliases	ATPIA
Ensembl gene	ENSG00000124406
Ensembl biotype	protein_coding
OMIM	609542
Entrez	10396

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000264449, ENST00000381668, ENST00000504024, ENST00000504510, ENST00000506602, ENST00000506713, ENST00000510289, ENST00000511858, ENST00000514372, ENST00000515872, ENST00000700470, ENST00000905751, ENST00000905752, ENST00000905753

RefSeq mRNA: 6 — MANE Select: NM_006095 NM_001105529, NM_001400024, NM_001400025, NM_001400026, NM_001400027, NM_006095

CCDS: CCDS3466, CCDS47049, CCDS93493

Canonical transcript exons

ENST00000381668 — 37 exons

Exon	Start	End
ENSE00000713326	42625614	42625713
ENSE00000846905	42485496	42485668
ENSE00000846906	42503450	42503514
ENSE00000846907	42507016	42507154
ENSE00000846908	42522160	42522299
ENSE00000846909	42524763	42524847
ENSE00000846910	42543917	42543986
ENSE00000846911	42549013	42549062
ENSE00000846912	42551198	42551280
ENSE00000846913	42552505	42552610
ENSE00000846914	42555968	42556040
ENSE00000846918	42624536	42624634
ENSE00001077408	42578260	42578387
ENSE00001077409	42600478	42600518
ENSE00001077412	42569161	42569205
ENSE00001077414	42581621	42581732
ENSE00001077415	42590811	42590884
ENSE00001077416	42575622	42575699
ENSE00001077417	42616033	42616078
ENSE00001077418	42579813	42579978
ENSE00001388334	42626995	42627109
ENSE00001411120	42656825	42657105
ENSE00001736911	42574619	42574707
ENSE00003466657	42446583	42446644
ENSE00003470796	42455525	42455599
ENSE00003472640	42408373	42413013
ENSE00003476629	42414627	42414718
ENSE00003481655	42464893	42465076
ENSE00003507436	42451981	42452059
ENSE00003520816	42443565	42443672
ENSE00003521734	42423617	42423705
ENSE00003543214	42455297	42455419
ENSE00003567806	42586349	42586476
ENSE00003596354	42464690	42464800
ENSE00003669322	42422807	42422899
ENSE00003682082	42588260	42588329
ENSE00003690699	42444578	42444634

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9536 / max 750.8113, expressed in 1105 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51977	15.0222	993
51976	4.5471	665
51974	3.0102	424
51975	0.7798	256
51973	0.5942	180

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.17	gold quality
corpus callosum	UBERON:0002336	99.08	gold quality
endothelial cell	CL:0000115	98.95	gold quality
CA1 field of hippocampus	UBERON:0003881	98.47	gold quality
inferior vagus X ganglion	UBERON:0005363	98.08	gold quality
middle frontal gyrus	UBERON:0002702	97.82	gold quality
orbitofrontal cortex	UBERON:0004167	97.48	gold quality
lateral globus pallidus	UBERON:0002476	97.38	gold quality
subthalamic nucleus	UBERON:0001906	97.31	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.29	gold quality
medulla oblongata	UBERON:0001896	97.12	gold quality
superior frontal gyrus	UBERON:0002661	96.99	gold quality
entorhinal cortex	UBERON:0002728	96.99	gold quality
parietal lobe	UBERON:0001872	96.98	gold quality
postcentral gyrus	UBERON:0002581	96.93	gold quality
middle temporal gyrus	UBERON:0002771	96.85	gold quality
superior vestibular nucleus	UBERON:0007227	96.65	gold quality
primary visual cortex	UBERON:0002436	96.62	gold quality
occipital lobe	UBERON:0002021	96.57	gold quality
inferior olivary complex	UBERON:0002127	96.50	gold quality
trigeminal ganglion	UBERON:0001675	96.47	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.38	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.14	gold quality
ventral tegmental area	UBERON:0002691	95.82	gold quality
pigmented layer of retina	UBERON:0001782	95.69	gold quality
frontal pole	UBERON:0002795	95.69	gold quality
retina	UBERON:0000966	95.66	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.60	gold quality
cortical plate	UBERON:0005343	95.60	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	79.32
E-HCAD-25	yes	48.82
E-ANND-3	yes	16.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, FOXO3

miRNA regulators (miRDB)

284 targeting ATP8A1, 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-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Literature-anchored findings (GeneRIF, showing 12)

• APLT has a role in macrophage-induced nitrosylation/oxidation plays an important role in cell clearance (PMID:17229723)
• the phospholipid flippase complex of ATP8A1 and CDC50A proteins has a role in cell migration (PMID:23269685)
• Depletion of ATP8A1 impaired the asymmetric transbilayer distribution of phosphatidylserine in recycling endosomes, dissociated EHD1 from recycling endosomes, and generated aberrant endosomal tubules that appear resistant to fission. (PMID:25595798)
• The increased level of intracellular ATP8A1 protein attenuated the inhibitor role of miR-140-3p in the growth and mobility of NSCLC cell. (PMID:26415732)
• A pronounced induction of the flippase Atp8a1 was observed in post-mortem tissue homogenates from the hippocampus and temporal lobe of juvenile autistic subjects compared to age-matched controls. (PMID:27287255)
• Knockdown of ATP8A1 (a recycling endosome phosphatidlyserine-flippase) suppresses nuclear localization of YAP and YAP-dependent transcription. ATP8A1 knockdown increases the phosphorylated (activated) form of Lats1 that phosphorylates and inactivates YAP. (PMID:29093443)
• Single-nucleotide polymorphism, rs17448506, located in ATP8A1 intron, reached the significance threshold for interaction with tobacco smoke expose and bronchial hyperresponsiveness (p=10-5). (PMID:30282721)
• Over-expression of ATP8A1 alleviated ethanol-induced hepatocyte injury. Moreover, the PI3K/Akt signaling pathway appears to participate in inhibition of ethanol-induced hepatocyte apoptosis. (PMID:30457983)
• ATP8A1 is cleaved by the cysteine protease calpain during apoptosis, and the cleavage is prevented indirectly by caspase inhibition, involving blockage of calcium influx into platelets and subsequent calpain activation. (PMID:30674456)
• cryo-electron microscopy structure of six intermediates of the human flippase ATP8A1 bound to the partner protein CDC50a; ATP binding and autophosphorylation of ATP8A1 drive a cycle of conformations in which lipids bind differently, powering translocation. (PMID:31416931)
• AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells. (PMID:33990468)
• Exosome circATP8A1 induces macrophage M2 polarization by regulating the miR-1-3p/STAT6 axis to promote gastric cancer progression. (PMID:38459596)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp8a1	ENSDARG00000063001
danio_rerio	ATP8A1	ENSDARG00000114495
mus_musculus	Atp8a1	ENSMUSG00000037685
rattus_norvegicus	Atp8a1	ENSRNOG00000034200
rattus_norvegicus		ENSRNOG00000083562
drosophila_melanogaster	CG31729	FBGN0051729
caenorhabditis_elegans	tat-5	WBGENE00009498
caenorhabditis_elegans		WBGENE00017174

Paralogs (13): ATP9A (ENSG00000054793), ATP11B (ENSG00000058063), ATP11A (ENSG00000068650), ATP8B1 (ENSG00000081923), ATP11C (ENSG00000101974), ATP8B4 (ENSG00000104043), ATP10B (ENSG00000118322), ATP8B3 (ENSG00000130270), ATP8A2 (ENSG00000132932), ATP8B2 (ENSG00000143515), ATP10D (ENSG00000145246), ATP9B (ENSG00000166377), ATP10A (ENSG00000206190)

Protein

Protein identifiers

Phospholipid-transporting ATPase IA — Q9Y2Q0 (reviewed: Q9Y2Q0)

Alternative names: ATPase class I type 8A member 1, Chromaffin granule ATPase II, P4-ATPase flippase complex alpha subunit ATP8A1

All UniProt accessions (5): Q9Y2Q0, H0Y8I6, H0YAA1, H0YAJ4, Q4G1C1

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation also seems to be implicated in vesicle formation and in uptake of lipid signaling molecules. In vitro, its ATPase activity is selectively and stereospecifically stimulated by phosphatidylserine (PS). The flippase complex ATP8A1:TMEM30A seems to play a role in regulation of cell migration probably involving flippase-mediated translocation of phosphatidylethanolamine (PE) at the cell membrane. Acts as aminophospholipid translocase at the cell membrane in neuronal cells.

Subunit / interactions. Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit and an accessory beta subunit. Interacts with TMEM30A to form a flippase complex; this complex forms an intermediate phosphoenzyme. Interacts with TMEM30B; this interaction is reported conflictingly.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Chromaffin granule membrane. Cytoplasmic granule. Cell membrane. Endoplasmic reticulum. Golgi apparatus.

Tissue specificity. Found in most adult tissues except liver, testis and placenta. Most abundant in heart, brain and skeletal muscle. Also detected in fetal tissues. Isoform 1 is only detected in brain, skeletal muscle and heart and is the most abundant form in skeletal muscle. Highly expressed in platelets.

Post-translational modifications. Cleaved by calpain in a caspase- and calcium influx-dependent manner during platelet apoptosis leading to a 100 kDa polypeptide.

Activity regulation. ATPase activity is stimulated by phosphatidylserine (PS) and minimally by phosphatidylethanolamine (PE). ATPase activity is inhibited by beryllium fluoride and aluminum trifluoride.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y2Q0-1	1, Long	yes
Q9Y2Q0-2	2, Short
Q9Y2Q0-3	3

RefSeq proteins (6): NP_001098999, NP_001386953, NP_001386954, NP_001386955, NP_001386956, NP_006086* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001757	P_typ_ATPase	Family
IPR006539	P-type_ATPase_IV	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
IPR032630	P_typ_ATPase_c	Domain
IPR032631	P-type_ATPase_N	Domain
IPR036412	HAD-like_sf	Homologous_superfamily
IPR044492	P_typ_ATPase_HD_dom	Domain
IPR059000	ATPase_P-type_domA	Domain

Pfam: PF00122, PF13246, PF16209, PF16212

Enzyme classification (BRENDA):

• EC 7.6.2.1 — P-type phospholipid transporter (BRENDA: 22 organisms, 260 substrates, 62 inhibitors, 53 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.016–2.215	41
P-NITROPHENYL PHOSPHATE	1.17–1.46	3
ACETYL PHOSPHATE	1.03–1.31	2
1-PALMITOYL-2-OLEOYL-SN-GLYCERO-3-PHOSPHO-L-SERI	0.111	1

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) + ATP + H2O = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) + ADP + phosphate + H(+) (RHEA:38567)

UniProt features (153 total): helix 45, strand 45, binding site 20, topological domain 11, transmembrane region 10, turn 9, modified residue 5, site 2, splice variant 2, chain 1, active site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6K7L	ELECTRON MICROSCOPY	2.83
6K7N	ELECTRON MICROSCOPY	2.84
6K7M	ELECTRON MICROSCOPY	2.95
6K7K	ELECTRON MICROSCOPY	3.04
6K7J	ELECTRON MICROSCOPY	3.08
6K7H	ELECTRON MICROSCOPY	3.22
6K7I	ELECTRON MICROSCOPY	3.22
6K7G	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2Q0-F1	82.58	0.36

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 (3): 409 (4-aspartylphosphate intermediate); 352 (involved in the recognition of the lipid substrate on the exoplasmic side); 357 (involved in the release of the transported lipid into the cytosolic leaflet)

Ligand- & substrate-binding residues (20): 409; 409; 410; 411; 411; 508; 549; 572; 605; 685; 686; 687 …

Post-translational modifications (5): 25, 28, 29, 443, 1126

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 408 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, IVANOVA_HEMATOPOIESIS_MATURE_CELL, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_POSITIVE_REGULATION_OF_LIPID_TRANSPORT, GOBP_SYNAPTIC_VESICLE_RECYCLING, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, BROWNE_HCMV_INFECTION_24HR_UP

GO Biological Process (12): learning (GO:0007612), positive regulation of cell migration (GO:0030335), monoatomic ion transmembrane transport (GO:0034220), phospholipid translocation (GO:0045332), synaptic vesicle endocytosis (GO:0048488), positive regulation of phospholipid translocation (GO:0061092), aminophospholipid translocation (GO:0140331), transport across blood-brain barrier (GO:0150104), lipid transport (GO:0006869), phospholipid transport (GO:0015914), lipid translocation (GO:0034204), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (11): magnesium ion binding (GO:0000287), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ATPase-coupled monoatomic cation transmembrane transporter activity (GO:0019829), phosphatidylserine floppase activity (GO:0090556), ATPase-coupled intramembrane lipid carrier activity (GO:0140326), phosphatidylserine flippase activity (GO:0140346), nucleotide binding (GO:0000166), transporter activity (GO:0005215), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (20): endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), synaptic vesicle membrane (GO:0030672), organelle membrane (GO:0031090), cytoplasmic vesicle (GO:0031410), azurophil granule membrane (GO:0035577), specific granule membrane (GO:0035579), chromaffin granule membrane (GO:0042584), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), phospholipid-translocating ATPase complex (GO:1990531), endomembrane system (GO:0012505), cytoplasmic vesicle membrane (GO:0030659), synapse (GO:0045202), bounding membrane of organelle (GO:0098588), secretory vesicle (GO:0099503)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
Ion channel transport	1
Immune System	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	3
secretory granule membrane	3
phospholipid translocation	2
lipid transport	2
ATP-dependent activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
membrane	2
cytoplasmic vesicle	2
learning or memory	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
monoatomic ion transport	1
transmembrane transport	1
phospholipid transport	1
lipid translocation	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
positive regulation of cellular component organization	1
regulation of phospholipid translocation	1
positive regulation of phospholipid transport	1
aminophospholipid transport	1
vascular transport	1
transport	1
lipid localization	1
organophosphate ester transport	1
regulation of membrane lipid distribution	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
monoatomic cation transmembrane transporter activity	1
active monoatomic ion transmembrane transporter activity	1
ATPase-coupled transmembrane transporter activity	1
floppase activity	1
intramembrane lipid carrier activity	1

Protein interactions and networks

STRING

1282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP8A1	CDC50A	Q9NV96	989
ATP8A1	GRXCR1	A8MXD5	927
ATP8A1	ACADM	P11310	714
ATP8A1	CDC50B	Q3MIR4	605
ATP8A1	PLEKHB2	Q96CS7	541
ATP8A1	EHD1	Q9H4M9	507
ATP8A1	IFT27	Q9BW83	415
ATP8A1	SHISA3	A0PJX4	401
ATP8A1	ANKLE1	Q8NAG6	399
ATP8A1	NEO1	Q92859	395
ATP8A1	MYO6	Q9UM54	386
ATP8A1	DVL1	O14640	370
ATP8A1	SLC17A8	Q8NDX2	367
ATP8A1	WFS1	O76024	366
ATP8A1	KLHL26	Q53HC5	357

IntAct

34 interactions, top by confidence:

A	B	Type	Score
TMEM30A	ATP8A1	psi-mi:“MI:0915”(physical association)	0.740
ATP8A1	TMEM30A	psi-mi:“MI:0915”(physical association)	0.740
ATP8A1	TMEM30A	psi-mi:“MI:0403”(colocalization)	0.740
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
ATP8A1	TMEM30B	psi-mi:“MI:0915”(physical association)	0.460
ATP8A1	TMEM30B	psi-mi:“MI:0403”(colocalization)	0.460
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC6A20	TLCD2	psi-mi:“MI:0914”(association)	0.350
SLC17A2	ABCD4	psi-mi:“MI:0914”(association)	0.350
FLVCR2	PLPP1	psi-mi:“MI:0914”(association)	0.350
MFSD12	SNAP23	psi-mi:“MI:0914”(association)	0.350
MFSD4A	TIMM23	psi-mi:“MI:0914”(association)	0.350
SLC16A10	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC19A1	TAPBP	psi-mi:“MI:0914”(association)	0.350
SLC19A3	SNAP23	psi-mi:“MI:0914”(association)	0.350
SLC2A1	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
SLC2A4	PTPRA	psi-mi:“MI:0914”(association)	0.350
SLC37A2	WWP2	psi-mi:“MI:0914”(association)	0.350
SLC38A9	SCAMP3	psi-mi:“MI:0914”(association)	0.350
SLC43A1	PLPP1	psi-mi:“MI:0914”(association)	0.350
SLC43A3	PLPP3	psi-mi:“MI:0914”(association)	0.350
SLC47A1	PLOD2	psi-mi:“MI:0914”(association)	0.350
SLC5A12	PLPP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): ATP8A1 (Affinity Capture-Western), ATP8A1 (Affinity Capture-MS), ATP8A1 (Affinity Capture-RNA), ATP8A1 (Proximity Label-MS), ATP8A1 (Proximity Label-MS), ATP8A1 (Proximity Label-MS), ATP8A1 (Affinity Capture-MS), ATP8A1 (Affinity Capture-MS), ATP8A1 (Affinity Capture-MS), ATP8A1 (Proximity Label-MS), ATP8A1 (Affinity Capture-MS), ATP8B3 (Negative Genetic), ATP8A2 (Negative Genetic), PFN1 (Cross-Linking-MS (XL-MS)), ATP8A1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2YFN7, B8AJT9, C7EXK4, D3K5L7, E1C6Q1, E2R222, O70133, O70496, O94973, O95544, P51798, P51799, P70704, P97834, P98200, Q0VCK5, Q10D38, Q13098, Q15645, Q304A0, Q3UA06, Q4PKH3, Q5JQD7, Q5XHZ9, Q5XIJ5, Q5ZJL4, Q61187, Q67UQ7, Q6DD70, Q6EPN6, Q6GL10, Q6IRE4, Q6NRT5, Q8L5Y9, Q99JW1, Q99K70, Q99LD4, Q9FLG2, Q9HB90, Q9HCX4

Diamond homologs: A1A4J6, A3FIN4, D4ABB8, F1Q4S1, G2X7W6, G5EBH1, O43861, O70228, O75110, O94296, P05025, P13607, P25489, P35317, P39524, P40527, P57792, P70704, P98195, P98196, P98197, P98198, P98199, P98205, Q10309, Q29449, Q6DFW5, Q6RWA9, Q8TF62, Q92123, Q9GKS6, Q9LK90, Q9N0Z4, Q9NTI2, Q9Y2G3, Q9Y2Q0, Q9YH26, S7VVK4, B1AWN4, C7EXK4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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
R-HSA-425393	5	19.1×	3e-04
SLC-mediated transmembrane transport	8	13.9×	1e-05
Transport of small molecules	9	6.7×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
transport across blood-brain barrier	6	25.6×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	105
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
4070956	NM_006095.2(ATP8A1):c.2147T>C (p.Leu716Pro)	Pathogenic
562874	GRCh37/hg19 4p16.3-11(chr4:68345-49089361)x3	Pathogenic

SpliceAI

6436 predictions. Top by Δscore:

Variant	Effect	Δscore
4:42414625:A:AC	donor_gain	1.0000
4:42414626:C:CC	donor_gain	1.0000
4:42414626:CGGAG:C	donor_gain	1.0000
4:42414727:CAGG:C	acceptor_gain	1.0000
4:42414730:G:C	acceptor_gain	1.0000
4:42422803:TTA:T	donor_loss	1.0000
4:42422804:TACC:T	donor_loss	1.0000
4:42422805:ACCT:A	donor_loss	1.0000
4:42422806:C:CG	donor_loss	1.0000
4:42422895:TGATA:T	acceptor_gain	1.0000
4:42422896:GATA:G	acceptor_gain	1.0000
4:42422897:ATA:A	acceptor_gain	1.0000
4:42422898:TA:T	acceptor_gain	1.0000
4:42422899:ACTG:A	acceptor_loss	1.0000
4:42422900:C:CC	acceptor_gain	1.0000
4:42422900:C:CG	acceptor_loss	1.0000
4:42422903:C:CT	acceptor_gain	1.0000
4:42422904:A:T	acceptor_gain	1.0000
4:42423615:A:AC	donor_gain	1.0000
4:42423616:C:CC	donor_gain	1.0000
4:42444631:CAAA:C	acceptor_gain	1.0000
4:42444635:C:CC	acceptor_gain	1.0000
4:42445111:TAAA:T	donor_gain	1.0000
4:42445112:AAAA:A	donor_gain	1.0000
4:42446581:A:AC	donor_gain	1.0000
4:42446582:C:CC	donor_gain	1.0000
4:42464796:TTGAA:T	acceptor_gain	1.0000
4:42464797:TGAA:T	acceptor_gain	1.0000
4:42464798:GAA:G	acceptor_gain	1.0000
4:42464801:C:CC	acceptor_gain	1.0000

AlphaMissense

7634 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:42413000:G:C	F1137L	1.000
4:42413000:G:T	F1137L	1.000
4:42413002:A:G	F1137L	1.000
4:42455528:G:C	N897K	1.000
4:42455528:G:T	N897K	1.000
4:42464711:A:C	N866K	1.000
4:42464711:A:T	N866K	1.000
4:42464714:C:A	K865N	1.000
4:42464714:C:G	K865N	1.000
4:42464715:T:A	K865M	1.000
4:42464766:C:T	G848D	1.000
4:42464934:C:G	G823R	1.000
4:42464960:A:T	V814D	1.000
4:42464986:A:C	D805E	1.000
4:42464986:A:T	D805E	1.000
4:42464987:T:A	D805V	1.000
4:42464987:T:C	D805G	1.000
4:42464987:T:G	D805A	1.000
4:42464988:C:G	D805H	1.000
4:42464989:A:C	N804K	1.000
4:42464989:A:T	N804K	1.000
4:42464996:C:T	G802E	1.000
4:42464997:C:G	G802R	1.000
4:42464997:C:T	G802R	1.000
4:42464999:T:A	D801V	1.000
4:42464999:T:C	D801G	1.000
4:42464999:T:G	D801A	1.000
4:42465000:C:G	D801H	1.000
4:42465002:C:A	G800V	1.000
4:42465002:C:T	G800D	1.000

dbSNP variants (sampled 300 via entrez): RS1000027031 (4:42412623 C>T), RS10000302 (4:42528729 C>T), RS1000035794 (4:42431134 T>C,G), RS1000043545 (4:42578835 A>G), RS1000056279 (4:42511311 T>C), RS10000708 (4:42473335 T>A,C,G), RS1000084040 (4:42592534 T>C), RS1000099095 (4:42620370 T>C), RS1000114460 (4:42448219 T>G), RS1000118315 (4:42426948 A>G), RS1000124010 (4:42598235 T>C), RS1000124442 (4:42463095 C>T), RS1000141655 (4:42579169 C>A), RS1000143563 (4:42598033 C>G,T), RS1000146347 (4:42620574 C>A)

Disease associations

OMIM: gene MIM:609542 | disease phenotypes: MIM:143890

GenCC curated gene-disease

Mondo (2): autism spectrum disorder (MONDO:0005258), hypercholesterolemia, familial, 1 (MONDO:0007750)

Orphanet (2): Homozygous familial hypercholesterolemia (Orphanet:391665), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001538_29	Immune reponse to smallpox (secreted IFN-alpha)	2.000000e-07
GCST002666_5	Interferon alpha levels in systemic lupus erythematosus	2.000000e-06
GCST004125_6	Type 2 diabetes (age of onset)	2.000000e-06
GCST004738_2	Duloxetine response in major depressive disorder (% change in symptom score)	8.000000e-06
GCST006522_13	Upper eyelid sagging severity	2.000000e-06
GCST006522_14	Upper eyelid sagging severity	9.000000e-07
GCST006575_31	Takayasu arteritis	2.000000e-06
GCST010456_1	Anthracycline-induced cardiotoxicity in early breast cancer	4.000000e-06
GCST011741_28	LDL cholesterol levels in HIV infection	1.000000e-05
GCST012051_1	Systolic blood pressure	1.000000e-07

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0006517	interferon alpha measurement
EFO:0005257	response to anthracycline-based chemotherapy
EFO:1001482	cardiotoxicity
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0006335	systolic blood pressure

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 — P4 P-type ATPases: Phospholipid-transporting ATPases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	4
(+)-JQ1 compound	decreases expression, increases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment, increases expression	3
trichostatin A	affects expression, decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Calcitriol	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
lead acetate	decreases expression	1
manganese chloride	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, increases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Chenodeoxycholic Acid	affects cotreatment, increases expression	1
Copper	affects binding, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder