ATP8A2

protein-coding

ATPase phospholipid transporting 8A2, the group of ATPase phospholipid transporting

Gene summary

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. [provided by RefSeq, Jul 2017]

MANE transcript

NM_016529.6

Inheritance

ClinVar variants

P:58U:233B:135

Top phenotype

Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr13:25,371,974-26,025,851

External References & Databases

Ensembl (ENSG00000132932)

Transcript & Mutation Effects

hg38 • Region Span ~653.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014104

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014104

Submitter: G2P

cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014104

Submitter: PanelApp Australia

cerebellar ataxia, intellectual disability, and dysequilibriumDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009133

Submitter: ClinGen

*ATP8A2* was first reported in relation to autosomal recessive cerebellar ataxia, intellectual disability, and disequilibrium syndrome (CAMRQ) in 2018 (Alsahli S, et al., PMID: 29531481). Phenotypic features reported in affected individuals include ataxia, hypotonia, and intellectual impairment. Other features include absent deep tendon reflexes, hyperreflexia, speech and language delays, dysarthria, inability to walk, ataxic gait, and dyskinetic quadriplegia, with some individuals presenting with quadrupedal locomotion. Atrophy of the cerebral, cerebellar, and corpus callosum is also observed. Hearing loss is noted in some individuals, while eye-related issues include nystagmus, optic atrophy, retinal degeneration, blepharoptosis, and ptosis. Nine variants (missense, nonsense and frameshift) reported in eight probands in six publications (PMIDs: 38109455, 35321980, 33079427, 29531481, 39066872, 30012219) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function, with the phenotypic severity depending on the protein's localization and protein misfolding (PMID: 38436085). This gene-disease relationship is also supported by experimental evidence such as a mouse model. In Zhu et al, *ATP8A2* was identified to be the causative gene in Wabbler-lethal mutant mice presenting with axonal degeneration (PMID: 22912588). RT-PCR analysis revealed *ATP8A2* is widely expressed in the cerebrum, cerebellum, spinal cord and retina. The study also demonstrated that *ATP8A2* is a phospholipid translocase, and the mutant protein failed to retain its function (PMID: 22912588). In summary, there is definitive evidence to support the relationship between *ATP8A2* and autosomal recessive cerebellar ataxia, intellectual disability, and dysequilibrium (CAMRQ). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on April 3, 2025 (SOP Version 11).

cerebellar ataxia, intellectual disability, and dysequilibriumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009133

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22892528

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP8A2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 416

Inborn genetic diseasesTotal: 116

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4Total: 62

not specifiedTotal: 46

ATP8A2-related disorderTotal: 19

Severe intellectual deficiencyTotal: 1

Dysequilibrium syndromeTotal: 1

EpilepsyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016529.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	117 clinvar	6 clinvar	125
missense	1 clinvar	7 clinvar	229 clinvar	11 clinvar	1 clinvar	249
nonsense	5 clinvar	8 clinvar	2 clinvar			15
start loss						0
frameshift	9 clinvar	8 clinvar				17
splice donor/acceptor (+/-2bp)	3 clinvar	17 clinvar				20
Total	18	40	233	128	7	426

Highest pathogenic variant AF is 0.000024164437

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016529.6	RefSeq	NP_057613.4	37	MANE Select
ENST00000381655.7	Ensembl	ENSP00000371070.2	37	MANE Select
NM_001313741.1	RefSeq	NP_001300670.1	35	Standard
NM_001411005.1	RefSeq	NP_001397934.1	36	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ion channel transport
Transport of small molecules
Ion transport by P-type ATPases

Biological Process

involuntary skeletal muscle contraction
axonogenesis
aging
negative regulation of cell population proliferation
retina layer formation

Molecular Function

magnesium ion binding
phospholipid-translocating ATPase activity
ATP binding

Cellular Component

photoreceptor outer segment
nucleoplasm
endosome
Golgi apparatus
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381655
Coding exons: 37
Length: 653781
Individuals with no LoFs: 124752
Homozygous LoFs: 0
Heterozygous LoFs: 58
Defined: 124810
p: 0.000232

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.30	490	655	0.748	0.0000357	7721
Missense (PolyPhen)		163	268.7	0.60663		3366
Synonymous	0.614	240	252	0.951	0.0000151	2274
Loss of Function	4.39	33	73.7	0.448	0.00000370	883

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00039	0.00039	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00016	0.00016	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. Reconstituted to liposomes, the ATP8A2:TMEM30A flippase complex predomiminantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). 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. Involved in regulation of neurite outgrowth; acting in synergy with TMEM30A. Required for normal visual and auditory function; involved in photoreceptor and inner ear spiral ganglion cell survival.;
Disease: DISEASE: Note=A chromosomal aberration disrupting ATP8A2 has been found in a patient with severe mental retardation and major hypotonia. Translocation t(10;13)(p12.1;q12.13) (PubMed:20683487). {ECO:0000269|PubMed:20683487}.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.374
RVIS EVS: -1.1
RVIS percentile EVS: 6.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.282

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium