ATP8A2

Summary

ATP8A2 (ATPase phospholipid transporting 8A2, HGNC:13533) is a protein-coding gene on chromosome 13q12.13, encoding Phospholipid-transporting ATPase IB (Q9NTI2). 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 protein encoded by this gene is a member of the P4 ATPase family of proteins, which are thought to be involved in a process called lipid flipping, whereby phospholipids are translocated inwards from the exoplasmic leaflet to the cytosolic leaflet of the cell membrane, which aids in generating and maintaining asymmetry in membrane lipids. This protein is predicted to contain an E1 E2 ATPase, a haloacid dehalogenase-like hydrolase (HAD) domain, and multiple transmembrane domains. Associations between this protein and cell cycle control protein 50A are important for translocation of phosphatidylserine across membranes. Mutations in this gene have been associated with a syndrome (CAMRQ4) characterized by cerebellar ataxia and cognitive disabilities. In addition, a translocation breakpoint within this gene was observed in an individual with neurological dysfunction. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 51761 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar ataxia, intellectual disability, and dysequilibrium (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 579 total — 20 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 23
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_016529

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13533
Approved symbol	ATP8A2
Name	ATPase phospholipid transporting 8A2
Location	13q12.13
Locus type	gene with protein product
Status	Approved
Aliases	ATPIB, ML-1
Ensembl gene	ENSG00000132932
Ensembl biotype	protein_coding
OMIM	605870
Entrez	51761

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 6 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 5 retained_intron, 3 protein_coding

ENST00000281620, ENST00000381648, ENST00000381655, ENST00000491840, ENST00000682472, ENST00000682580, ENST00000682942, ENST00000682943, ENST00000683303, ENST00000683455, ENST00000683461, ENST00000683845, ENST00000683868, ENST00000683945, ENST00000683960, ENST00000684025, ENST00000684283, ENST00000684424, ENST00000684551

RefSeq mRNA: 4 — MANE Select: NM_016529 NM_001313741, NM_001411005, NM_001411006, NM_016529

CCDS: CCDS41873, CCDS91792, CCDS91793

Canonical transcript exons

ENST00000381655 — 37 exons

Exon	Start	End
ENSE00001002177	25540319	25540388
ENSE00001002179	25543291	25543402
ENSE00001002181	25551338	25551503
ENSE00001002182	25553793	25553920
ENSE00001002183	25541919	25542046
ENSE00001002184	25537988	25538061
ENSE00001002185	25554991	25555068
ENSE00001144543	25559721	25559765
ENSE00001161708	25563956	25564031
ENSE00001423490	25371974	25372288
ENSE00001489373	26019888	26025851
ENSE00001764388	25558973	25559061
ENSE00003462222	25860195	25860256
ENSE00003476618	25699173	25699345
ENSE00003476993	25581819	25581957
ENSE00003501464	25961575	25961663
ENSE00003507325	25860804	25860860
ENSE00003508021	25769046	25769229
ENSE00003523935	25533273	25533313
ENSE00003524750	25532272	25532317
ENSE00003542966	25968575	25968679
ENSE00003557895	25774849	25774959
ENSE00003566738	25570767	25570872
ENSE00003575045	25571610	25571692
ENSE00003585348	25578815	25578899
ENSE00003590537	25589635	25589699
ENSE00003603007	25828118	25828192
ENSE00003609761	25530562	25530660
ENSE00003625159	25529999	25530098
ENSE00003629051	25839546	25839624
ENSE00003638625	25579808	25579947
ENSE00003643511	25862301	25862408
ENSE00003643793	25574808	25574857
ENSE00003645073	25577069	25577138
ENSE00003658608	25468977	25469121
ENSE00003672385	25837163	25837285
ENSE00003686228	26012531	26012622

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 97.20.

FANTOM5 (CAGE): breadth broad, TPM avg 4.1546 / max 343.4573, expressed in 321 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134473	2.3231	215
134478	1.0818	216
134477	0.3238	117
134474	0.2738	89
134475	0.1151	60
134472	0.0323	18
134479	0.0047	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	97.20	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.27	gold quality
orbitofrontal cortex	UBERON:0004167	95.06	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.35	gold quality
entorhinal cortex	UBERON:0002728	93.03	gold quality
postcentral gyrus	UBERON:0002581	92.67	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.45	gold quality
pons	UBERON:0000988	92.10	gold quality
sperm	CL:0000019	91.91	gold quality
parietal lobe	UBERON:0001872	91.68	gold quality
buccal mucosa cell	CL:0002336	91.56	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.42	silver quality
substantia nigra pars compacta	UBERON:0001965	91.38	gold quality
superior frontal gyrus	UBERON:0002661	91.27	gold quality
cortical plate	UBERON:0005343	90.81	gold quality
CA1 field of hippocampus	UBERON:0003881	90.48	silver quality
hair follicle	UBERON:0002073	89.83	silver quality
male germ cell	CL:0000015	89.69	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.34	gold quality
primary visual cortex	UBERON:0002436	87.82	gold quality
superior vestibular nucleus	UBERON:0007227	87.75	gold quality
dorsal root ganglion	UBERON:0000044	87.63	gold quality
inferior olivary complex	UBERON:0002127	87.31	gold quality
occipital lobe	UBERON:0002021	86.72	gold quality
lateral globus pallidus	UBERON:0002476	86.41	gold quality
cerebellum	UBERON:0002037	85.84	gold quality
cerebellar vermis	UBERON:0004720	85.75	gold quality
cerebellar cortex	UBERON:0002129	85.64	gold quality
cerebellar hemisphere	UBERON:0002245	85.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.68	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	2444.61
E-HCAD-35	yes	78.51
E-HCAD-25	yes	45.77
E-ENAD-17	yes	20.14
E-ANND-3	yes	6.30
E-MTAB-6386	no	5.32
E-MTAB-6678	no	3.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

274 targeting ATP8A2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1236-3P	99.94	68.04	1695

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 12)

• P4-ATPase Atp8a2 is a phosphatidylserine flippase in photoreceptor disc membranes (PMID:19778899)
• CDC50A is the beta-subunit of ATP8A2 and is crucial for the correct folding, stable expression, export from endoplasmic reticulum, and phosphatidylserine flippase activity of ATP8A2 (PMID:21454556)
• ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait. (PMID:22892528)
• Study describes a new ATP8A2 gene mutations associated with a novel syndrome that includes encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy. The data expand both the genetic and phenotypic spectrum associated with ATP8A2 gene mutations. (PMID:27679995)
• Using an electrophysiological method based on solid supported membranes, we observed the generation of a transient electrical current by the mammalian P4-ATPase ATP8A2 in the presence of ATP and the negatively charged lipid substrate phosphatidylserine, whereas only a diminutive current was generated with the lipid substrate phosphatidylethanolamine, which carries no or little charge under the conditions of the measuremen (PMID:31371510)
• Functional analysis of the effect of disease-associated missense mutations on ATP8A2 show that the p.Ile376Met and p.Lys429Met variants fold in a native-like conformation, but lack key amino acid residues required for ATP-dependent lipid transport. In contrast, the p.Lys429Asn, pAla544Pro, p.Arg625Trp, and p.Trp702Arg variants are highly misfolded and undergo rapid proteosomal degradation. (PMID:31397519)
• ATP8A2-related disorders as recessive cerebellar ataxia. (PMID:31612321)
• Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum. (PMID:33565221)
• Congenital ataxia due to novel variant in ATP8A2. (PMID:33682124)
• Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of ATP8A2. (PMID:35321980)
• On the track of the lipid transport pathway of the phospholipid flippase ATP8A2 - Mutation analysis of residues of the transmembrane segments M1, M2, M3 and M4. (PMID:37678495)
• Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases. (PMID:38436085)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp8a2	ENSDARG00000077492
mus_musculus	Atp8a2	ENSMUSG00000021983
rattus_norvegicus	Atp8a2	ENSRNOG00000008053
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), ATP8A1 (ENSG00000124406), ATP8B3 (ENSG00000130270), ATP8B2 (ENSG00000143515), ATP10D (ENSG00000145246), ATP9B (ENSG00000166377), ATP10A (ENSG00000206190)

Protein

Protein identifiers

Phospholipid-transporting ATPase IB — Q9NTI2 (reviewed: Q9NTI2)

Alternative names: ATPase class I type 8A member 2, ML-1, P4-ATPase flippase complex alpha subunit ATP8A2

All UniProt accessions (7): A0A804HI09, A0A804HJ19, A0A804HKN1, Q9NTI2, A0A804HKW9, A0A804HLG3, F8W9B3

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. Able to translocate phosphatidylserine, but not phosphatidylcholine. Phospholipid translocation also seems to be implicated in vesicle formation and in uptake of lipid signaling molecules. Reconstituted to liposomes, the ATP8A2:TMEM30A flippase complex predominantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). Phospholipid translocation is not associated with a countertransport of an inorganic ion or other charged substrate from the cytoplasmic side toward the exoplasm in connection with the phosphorylation from ATP. ATP8A2:TMEM30A may be involved in regulation of neurite outgrowth. Proposed to function in the generation and maintenance of phospholipid asymmetry in photoreceptor disk membranes and neuronal axon membranes. May be involved in vesicle trafficking in neuronal cells. Required for normal visual and auditory function; involved in photoreceptor and inner ear spiral ganglion cell survival.

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.

Subcellular location. Membrane. Golgi apparatus membrane. Endosome membrane. Cell membrane. Photoreceptor outer segment membrane. Photoreceptor inner segment membrane.

Tissue specificity. Strongly expressed in the brain, cerebellum, retina and testis.

Disease relevance. Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4 (CAMRQ4) [MIM:615268] An autosomal recessive, congenital cerebellar ataxia associated with dysarthia, quadrupedal gait and intellectual disability. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration disrupting ATP8A2 has been found in a patient with severe intellectual disability and major hypotonia. Translocation t(10;13)(p12.1;q12.13).

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NTI2-4	3	yes
Q9NTI2-1	1
Q9NTI2-3	2

RefSeq proteins (4): NP_001300670, NP_001397934, NP_001397935, NP_057613* (*=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), 2 shown:

• a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(in) + ATP + H2O = a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(out) + ADP + phosphate + H(+) (RHEA:36439)
• 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 (65 total): binding site 18, topological domain 11, transmembrane region 10, sequence variant 10, mutagenesis site 5, splice variant 3, site 2, chain 1, region of interest 1, compositionally biased region 1, active site 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NTI2-F1	81.12	0.33

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): 428 (4-aspartylphosphate intermediate); 371 (involved in the recognition of the lipid substrate on the exoplasmic side); 376 (involved in the release of the transported lipid into the cytosolic leaflet)

Ligand- & substrate-binding residues (18): 428; 428; 429; 430; 430; 528; 569; 592; 625; 705; 706; 707 …

Post-translational modifications (1): 45

Mutagenesis-validated functional residues (5):

Position	Phenotype
107	no effect on flippase activity toward phosphatidylserine. like the wild type, it is unable to translocate phosphatidylch
107	reduced flippase activity toward phosphatidylserine. like the wild type, it is unable to translocate phosphatidylcholine
429	abolishes atpase 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: 338 (showing top): GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_BEHAVIOR, MODULE_255, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, MODULE_317, GOBP_NEUROGENESIS, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, GOBP_NEURAL_RETINA_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_POSITIVE_REGULATION_OF_LIPID_TRANSPORT, MORF_RAD51L3, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (21): involuntary skeletal muscle contraction (GO:0003011), axonogenesis (GO:0007409), negative regulation of cell population proliferation (GO:0008285), determination of adult lifespan (GO:0008340), retina layer formation (GO:0010842), positive regulation of neuron projection development (GO:0010976), response to auditory stimulus (GO:0010996), positive regulation of multicellular organism growth (GO:0040018), inner ear morphogenesis (GO:0042472), eating behavior (GO:0042755), skin development (GO:0043588), phospholipid translocation (GO:0045332), neuron development (GO:0048666), neuromuscular process controlling posture (GO:0050884), detection of light stimulus involved in visual perception (GO:0050908), neurofilament cytoskeleton organization (GO:0060052), positive regulation of phospholipid translocation (GO:0061092), aminophospholipid translocation (GO:0140331), lipid transport (GO:0006869), phospholipid transport (GO:0015914), lipid translocation (GO:0034204)

GO Molecular Function (12): magnesium ion binding (GO:0000287), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), phosphatidylethanolamine flippase activity (GO:0090555), 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), aminophospholipid flippase activity (GO:0015247), metal ion binding (GO:0046872)

GO Cellular Component (14): Golgi membrane (GO:0000139), acrosomal vesicle (GO:0001669), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), endosome membrane (GO:0010008), sperm midpiece (GO:0097225), sperm annulus (GO:0097227), phospholipid-translocating ATPase complex (GO:1990531), endosome (GO:0005768), endomembrane system (GO:0012505), membrane (GO:0016020), cell projection (GO:0042995)

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	6
phospholipid translocation	2
ATP-dependent activity	2
glycerophospholipid flippase activity	2
bounding membrane of organelle	2
endomembrane system	2
sperm flagellum	2
skeletal muscle contraction	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
multicellular organismal process	1
neural retina development	1
anatomical structure formation involved in morphogenesis	1
retina morphogenesis in camera-type eye	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
response to mechanical stimulus	1
multicellular organism growth	1
regulation of multicellular organism growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
feeding behavior	1
animal organ development	1
phospholipid transport	1
lipid translocation	1
neuron differentiation	1
cell development	1
musculoskeletal movement	1
neuromuscular process	1
visual perception	1
detection of light stimulus involved in sensory perception	1
intermediate filament cytoskeleton organization	1

Protein interactions and networks

STRING

1576 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP8A2	RNF6	Q9Y252	853
ATP8A2	CDC50A	Q9NV96	737
ATP8A2	WDR81	Q562E7	641
ATP8A2	CDC50B	Q3MIR4	631
ATP8A2	SLC52A3	Q9NQ40	576
ATP8A2	ADAMTS18	Q8TE60	444
ATP8A2	TTLL5	Q6EMB2	437
ATP8A2	RHNO1	Q9BSD3	437
ATP8A2	S100A14	Q9HCY8	436
ATP8A2	DLEC1	Q9Y238	434
ATP8A2	POLR1F	Q3B726	429
ATP8A2	XKR8	Q9H6D3	428
ATP8A2	LZTS1	Q9Y250	426
ATP8A2	GLDC	P23378	418
ATP8A2	PWP1	Q13610	412

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TMEM30A	ATP8A2	psi-mi:“MI:0915”(physical association)	0.460
ATP8A2	TMEM30A	psi-mi:“MI:0403”(colocalization)	0.460
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): ATP8A2 (Co-fractionation), ATP8A2 (Affinity Capture-MS), ATP8A2 (Affinity Capture-MS), ATP8A2 (Proximity Label-MS), ATP8A2 (Negative Genetic), ZDHHC8 (Co-fractionation), DDX46 (Co-fractionation), EPN1 (Co-fractionation), NCKAP5L (Co-fractionation), ATP8A2 (Affinity Capture-Western), UIMC1 (Biochemical Activity)

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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	27
Uncertain significance	260
Likely benign	195
Benign	41

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323981	NM_016529.6(ATP8A2):c.2212-1G>C	Pathogenic
1526029	NM_016529.6(ATP8A2):c.709del (p.Thr237fs)	Pathogenic
1938648	NM_016529.6(ATP8A2):c.1110C>G (p.Tyr370Ter)	Pathogenic
1965531	NM_016529.6(ATP8A2):c.3361dup (p.Asp1121fs)	Pathogenic
2052322	NM_016529.6(ATP8A2):c.3296_3297delinsGCAAGCACAC (p.Thr1099fs)	Pathogenic
2113917	NM_016529.6(ATP8A2):c.1484del (p.Pro495fs)	Pathogenic
2444321	NM_016529.6(ATP8A2):c.1272T>G (p.Tyr424Ter)	Pathogenic
2504567	NM_016529.6(ATP8A2):c.1170_1174delinsAAGTATACTCAAGTATACTCAAGTATACTCAAGTATACTCAAGTATAC (p.Leu391fs)	Pathogenic
2628313	NM_016529.6(ATP8A2):c.1580-18C>G	Pathogenic
3244221	NC_000013.10:g.(?26043095)(26273503_?)del	Pathogenic
3338257	NM_016529.6(ATP8A2):c.649C>T (p.Gln217Ter)	Pathogenic
3339979	NM_016529.6(ATP8A2):c.3316dup (p.Glu1106fs)	Pathogenic
421706	NM_016529.6(ATP8A2):c.1787del (p.Asn596fs)	Pathogenic
426579	NM_016529.6(ATP8A2):c.1782+2T>C	Pathogenic
4694035	NM_016529.6(ATP8A2):c.812T>G (p.Leu271Ter)	Pathogenic
50946	NM_016529.6(ATP8A2):c.1128C>G (p.Ile376Met)	Pathogenic
800920	NM_016529.6(ATP8A2):c.1741C>T (p.Arg581Ter)	Pathogenic
802914	NM_016529.6(ATP8A2):c.2655del (p.Asn886fs)	Pathogenic
834056	NM_016529.6(ATP8A2):c.3183+1G>A	Pathogenic
976733	NM_016529.6(ATP8A2):c.691_701del (p.Leu231fs)	Pathogenic
1029608	NM_016529.6(ATP8A2):c.2158C>T (p.Arg720Ter)	Likely pathogenic
1029609	NM_016529.6(ATP8A2):c.3469+1G>C	Likely pathogenic
1323963	NM_016529.6(ATP8A2):c.1474-2del	Likely pathogenic
1495002	NM_016529.6(ATP8A2):c.3076-2A>G	Likely pathogenic
1526205	NM_016529.6(ATP8A2):c.518del (p.Gly173fs)	Likely pathogenic
1683935	NM_016529.6(ATP8A2):c.1185+5G>A	Likely pathogenic
1804808	NM_016529.6(ATP8A2):c.2842A>T (p.Lys948Ter)	Likely pathogenic
2100428	NM_016529.6(ATP8A2):c.2754+1G>A	Likely pathogenic
2436153	NM_016529.6(ATP8A2):c.1322dup (p.Lys442fs)	Likely pathogenic
2833294	NM_016529.6(ATP8A2):c.3075+1G>A	Likely pathogenic

SpliceAI

9397 predictions. Top by Δscore:

Variant	Effect	Δscore
13:25372285:GTGG:G	donor_gain	1.0000
13:25469118:TCAG:T	donor_loss	1.0000
13:25469119:CAG:C	donor_loss	1.0000
13:25469120:AGGT:A	donor_loss	1.0000
13:25469121:GG:G	donor_loss	1.0000
13:25469122:GT:G	donor_loss	1.0000
13:25469123:T:A	donor_loss	1.0000
13:25477289:A:G	acceptor_gain	1.0000
13:25529991:A:AG	acceptor_gain	1.0000
13:25529992:C:G	acceptor_gain	1.0000
13:25529997:A:AG	acceptor_gain	1.0000
13:25529997:AGTAC:A	acceptor_gain	1.0000
13:25529998:G:GC	acceptor_gain	1.0000
13:25529998:GT:G	acceptor_gain	1.0000
13:25529998:GTAC:G	acceptor_gain	1.0000
13:25529998:GTACG:G	acceptor_gain	1.0000
13:25530094:TACAG:T	donor_loss	1.0000
13:25530095:ACAGG:A	donor_loss	1.0000
13:25530096:CAGGT:C	donor_loss	1.0000
13:25530097:AGG:A	donor_loss	1.0000
13:25530098:GG:G	donor_loss	1.0000
13:25530099:GTAAT:G	donor_loss	1.0000
13:25530560:A:AG	acceptor_gain	1.0000
13:25530561:G:GG	acceptor_gain	1.0000
13:25530561:GC:G	acceptor_gain	1.0000
13:25530561:GCAA:G	acceptor_gain	1.0000
13:25530657:TTTT:T	donor_gain	1.0000
13:25530661:G:GG	donor_gain	1.0000
13:25532267:A:AG	acceptor_gain	1.0000
13:25532270:A:AG	acceptor_gain	1.0000

AlphaMissense

7777 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:25530072:T:C	F99L	1.000
13:25530074:C:A	F99L	1.000
13:25530074:C:G	F99L	1.000
13:25530075:T:C	F100L	1.000
13:25530077:T:A	F100L	1.000
13:25530077:T:G	F100L	1.000
13:25551417:T:C	L324P	1.000
13:25553831:T:C	F366L	1.000
13:25553833:C:A	F366L	1.000
13:25553833:C:G	F366L	1.000
13:25553853:T:C	L373P	1.000
13:25553858:C:A	P375T	1.000
13:25553858:C:T	P375S	1.000
13:25553859:C:A	P375H	1.000
13:25553859:C:G	P375R	1.000
13:25553864:A:C	S377R	1.000
13:25553866:T:A	S377R	1.000
13:25553866:T:G	S377R	1.000
13:25553868:T:C	L378P	1.000
13:25555049:T:C	L415P	1.000
13:25555061:T:A	L419H	1.000
13:25558991:G:C	D428H	1.000
13:25558992:A:C	D428A	1.000
13:25558992:A:G	D428G	1.000
13:25558992:A:T	D428V	1.000
13:25558994:A:C	K429Q	1.000
13:25558996:G:C	K429N	1.000
13:25558996:G:T	K429N	1.000
13:25559000:G:A	G431R	1.000
13:25559000:G:C	G431R	1.000

dbSNP variants (sampled 300 via entrez): RS1000007329 (13:25535234 T>G), RS1000009854 (13:25538129 T>G), RS1000028035 (13:25668607 A>G), RS1000031151 (13:25973287 G>C), RS1000033122 (13:25581188 T>C), RS1000034071 (13:25906935 T>A,C), RS1000037750 (13:25454646 G>A,C), RS1000042294 (13:25702489 G>A,C,T), RS1000053304 (13:25534942 A>G), RS1000054040 (13:25905314 G>C), RS1000057131 (13:25777243 A>G), RS1000060594 (13:25445915 G>A,T), RS1000060832 (13:25788929 A>G), RS1000062979 (13:25747148 A>G), RS1000063080 (13:25496572 A>T)

Disease associations

OMIM: gene MIM:605870 | disease phenotypes: MIM:615268, MIM:224050

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4	Strong	Autosomal recessive
cerebellar ataxia, intellectual disability, and dysequilibrium	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cerebellar ataxia, intellectual disability, and dysequilibrium	Definitive	AR

Mondo (3): cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (MONDO:0014104), epilepsy (MONDO:0005027), cerebellar ataxia, intellectual disability, and dysequilibrium (MONDO:0009133)

Orphanet (1): Dysequilibrium syndrome (Orphanet:1766)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000518	Cataract
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0002078	Truncal ataxia
HP:0002120	Cerebral cortical atrophy
HP:0002540	Inability to walk
HP:0003202	Skeletal muscle atrophy
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007371	Corpus callosum atrophy
HP:0009878	Cerebellar ataxia associated with quadrupedal gait
HP:0100021	Cerebral palsy
HP:0100022	Abnormality of movement

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001960_2	Eating disorders	8.000000e-07
GCST003672_3	Docetaxel-induced peripheral neuropathy in metastatic castrate-resistant prostate cancer	2.000000e-06
GCST005183_9	Common carotid intima-media thickness	7.000000e-06
GCST005586_8	Breast milk fatty acid composition (maternal genotype effect)	2.000000e-08
GCST005587_7	Breast milk fatty acid composition (infant genotype effect)	2.000000e-06
GCST009356_5	Nonsyndromic cleft palate	2.000000e-06
GCST009357_10	Nonsyndromic cleft lip	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005939	parental genotype effect measurement
EFO:0007959	fetal genotype effect measurement
EFO:0003959	cleft lip

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
C535731	Dysequilibrium syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — P4 P-type ATPases: Phospholipid-transporting ATPases

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
Benzo(a)pyrene	increases methylation, affects methylation	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Smoke	increases expression	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
Valproic Acid	affects expression, increases expression	2
bisphenol A	increases methylation, affects methylation, affects cotreatment	1
trichostatin A	decreases expression	1
1,6-hexamethylene diisocyanate	increases methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	decreases methylation	1
Methapyrilene	increases methylation	1
Progesterone	decreases expression, affects cotreatment	1
Silicon Dioxide	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	affects methylation	1
Okadaic Acid	decreases expression	1
S-Nitrosoglutathione	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1426	Mono-Mac-6	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy