GeneBe

ATP13A2

protein-coding

ATPase cation transporting 13A2, the group of ATPase orphan transporters

Gene summary

This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]

Previous symbols:
  • PARK9

MANE transcript

NM_022089.4

Inheritance

AR

ClinVar variants

P:101U:467B:383

Top phenotype

Kufor-Rakeb syndrome (Parkinson disease 9)

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr1:16,985,958-17,011,928

External References & Databases

Ensembl (ENSG00000159363)NCBI Gene (23400)OMIM (610513)HGNC:30213GenCCUniProt (Q9NQ11)AlphaFoldClinVar (ATP13A2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~26.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kufor-Rakeb syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011706

Submitter: ClinGen

*ATP13A2* was first reported in relation to autosomal recessive Kufor-Rakeb syndrome in 2006 (Ramirez et al., PMID: 16964263). It was later reported in relation to other autosomal recessive neurodegenerative disorders including hereditary spastic paraplegia, cerebellar ataxia, amyotrophic lateral sclerosis (ALS), and neuronal ceroid lipofuscinosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is insufficient evidence of a difference in molecular mechanisms or inheritance pattern to explain the wide phenotypic spectrum observed from *ATP13A2* variation; therefore, the Intellectual Disability and Autism Gene Curation Expert Panel decided to lump all these entities together and curate them under the umbrella term Kufor-Rakeb syndrome. Evidence supporting the relationship between *ATP13A2* and a complex movement disorder includes case-level data, segregation data, and experimental data. For the purposes of this curation, nine variants (missense, splicing, nonsense, and frameshift) reported in seven probands in six publications are included in this curation: (PMIDs: 16964263, 21696388, 27165006, 31944623, 33033738, 30992063). In addition, variants in this gene segregated with disease in at least three families (PMIDs: 11584046, 16964263, 21696388). More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be bi-allelic loss of function (LoF). This gene-disease association is also supported by animal models and in vitro functional assays (PMIDs: 22647602, 22442086, 23393156, 25855184, 30992063). In summary, *ATP13A2* is definitively associated with autosomal recessive Kufor-Rakeb syndrome. 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 Intellectual Disability and Autism Gene Curation Expert Panel on the meeting date April 14, 2022 (SOP Version 8).

autosomal recessive spastic paraplegia type 78STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014975

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive spastic paraplegia type 78MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014975

Submitter: Genomics England PanelApp

Kufor-Rakeb syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011706

Submitter: Labcorp Genetics (formerly Invitae)

Kufor-Rakeb syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011706

Submitter: G2P

autosomal recessive spastic paraplegia type 78SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014975

Submitter: Orphanet

parkinsonism due to ATP13A2 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017809

Submitter: Orphanet

Kufor-Rakeb syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011706

Submitter: Illumina

Kufor-Rakeb syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011706

Submitter: Genomics England PanelApp

autosomal recessive spastic paraplegia type 78STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014975

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Kufor-Rakeb syndrome (Parkinson disease 9)AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: In Kufor-Rakeb syndrome, response to levodopa has been documented

Refs: 16964263; 17485642; 20310007; 22388936; 27217339Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP13A2 variants in ClinVar

11 Conditions Cataloged
Kufor-Rakeb syndromeTotal: 975
Autosomal recessive spastic paraplegia type 78Total: 955
Inborn genetic diseasesTotal: 314
not providedTotal: 279
not specifiedTotal: 145
ATP13A2-related disorderTotal: 44
Neurodegeneration with brain iron accumulationTotal: 8
Hereditary ataxiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022089.4. 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.

EffectPLPVUSLBBSum
synonymous
20
clinvar
314
clinvar
4
clinvar
 338
missense
3
clinvar
6
clinvar
439
clinvar
65
clinvar
 513
nonsense
15
clinvar
12
clinvar
1
clinvar
 28
start loss
1
clinvar
 1
frameshift
29
clinvar
14
clinvar
3
clinvar
 46
splice donor/acceptor (+/-2bp)
1
clinvar
21
clinvar
3
clinvar
 25
Total48534673794951

Highest pathogenic variant AF is 0.00007993377

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 85 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_022089.4RefSeqNP_071372.129MANE Select
ENST00000326735.13EnsemblENSP00000327214.829MANE Select
NM_001141973.3RefSeqNP_001135445.129Standard
NM_001141974.3RefSeqNP_001135446.127Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
atp13a2Danio rerio

Structure: whole organism

Quality: increased curvature

abnormal

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

  • cellular calcium ion homeostasis
  • cellular iron ion homeostasis
  • cellular zinc ion homeostasis
  • regulation of mitochondrion organization
  • regulation of macroautophagy

Molecular Function

  • protein binding
  • ATP binding
  • zinc ion binding
  • ATPase activity
  • cation-transporting ATPase activity

Cellular Component

  • lysosome
  • lysosomal membrane
  • late endosome
  • multivesicular body
  • autophagosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000326735
Coding exons
29
Length
25971
Individuals with no LoFs
125647
Homozygous LoFs
0
Heterozygous LoFs
101
Defined
125748
p
0.000402
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.406247310.8540.00005087465
Missense (PolyPhen)186241.280.77092622
Synonymous-0.5373423301.040.00002432564
Loss of Function4.122457.80.4150.00000289620

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000500.00049rare
Latino/Admixed American0.000410.00040rare
Ashkenazi Jewish0.00250.0025notable
East Asian0.000270.00027rare
Finnish0.000100.000092rare
European (Non-Finnish)0.000320.00032rare
South Asian0.000200.00020rare
Other0.000820.00081rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: ATPase that plays a role in intracellular cation homeostasis and the maintenance of neuronal integrity (PubMed:22186024). Required for a proper lysosomal and mitochondrial maintenance (PubMed:22296644, PubMed:28137957). {ECO:0000269|PubMed:22186024, ECO:0000269|PubMed:22296644, ECO:0000269|PubMed:28137957}.;
Disease
DISEASE: Kufor-Rakeb syndrome (KRS) [MIM:606693]: A rare form of autosomal recessive juvenile or early-onset, levodopa-responsive parkinsonism. In addition to typical parkinsonian signs, clinical manifestations of Kufor-Rakeb syndrome include behavioral problems, facial tremor, pyramidal tract dysfunction, supranuclear gaze palsy, and dementia. {ECO:0000269|PubMed:16964263, ECO:0000269|PubMed:17485642, ECO:0000269|PubMed:18413573, ECO:0000269|PubMed:20683840, ECO:0000269|PubMed:20853184, ECO:0000269|PubMed:21542062, ECO:0000269|PubMed:22296644, ECO:0000269|PubMed:22388936, ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:28137957}. Note=The disease is caused by mutations affecting the gene represented in this entry. KRS has also been referred to as neuronal ceroid lipofuscinosis 12 (CLN12), due to neuronal and glial lipofuscin deposits detected in the cortex, basal nuclei and cerebellum of some patients. {ECO:0000269|PubMed:22388936}.; DISEASE: Spastic paraplegia 78, autosomal recessive (SPG78) [MIM:617225]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:27217339, ECO:0000269|PubMed:28137957}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.161

Intolerance Scores

LoFtool
0.0289
RVIS EVS
-1.16
RVIS percentile EVS
6.1

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.227

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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