Human Gene Module / Chromosome 20 / ATP9A

ATP9AATPase phospholipid transporting 9A

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 6
Rare Variants / Common Variants
15 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
20q13.2
Associated Disorders
-
Relevance to Autism

Cordovado et al., 2025 reported five individuals with de novo missense variants in the ATP9A gene presenting with non-syndromic intellectual disability characterized by developmental delay, language impairment, autistic features (including stereotyped movements and/or ritualized/rigid behavior), and epilepsy; functional studies demonstrated that overexpression of selected ATP9A missense variants in HeLa cells and primary neuronal cultures resulted in either retention in the endoplasmic reticulum or a loss of mature dendritic spines. A de novo loss-of-function variant and a de novo missense variant predicted to be deleterious have been reported in ATP9A in ASD probands from the SPARK cohort and the Autism Sequencing Consortium, respectively (Satterstrom et al., 2020; Zhou et al., 2022). Biallelic variants in the ATP9A gene are responsible for neurodevelopmental disorder with poor growth and behavioral abnormalities (NEDGBA; OMIM 20242), an autosomal recessive disorder characterized by global developmental delay, moderately to severely impaired intellectual development, often with absent speech, behavioral abnormalities (including hyperactivity, short attention span, and ADHD), and failure to thrive with poor overall growth; Mattioli et al., 2021 reported that one individual from a consanguineous Iranian family with a homozygous splice-site variant presented with autistic features and stereotyped movements in addition to features frequently associated with NEDGBA. Meng et al., 2023 found that Atp9a-null mice displayed behavioral abnormalities, including impaired muscle strength, impaired hippocampus-dependent spatial learning and memory, and hyperactive/hyperkinetic movements, as well as reduced dendritic arborization and reduced density of dendritic spines in pyramidal and hippocampal neurons.

Molecular Function

Enables protease binding activity. Involved in negative regulation of exosomal secretion; regulation of endocytic recycling; and regulation of retrograde transport, endosome to Golgi. Located in several cellular components, including endosome; perinuclear region of cytoplasm; and trans-Golgi network membrane. Implicated in neurodevelopmental disorder with poor growth and behavioral abnormalities.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
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Reports related to ATP9A (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Support - Francesca Mattioli et al. (2021) No Autistic features, stereotypy, ADHD, epilepsy/seiz
3 Support - Zhou X et al. (2022) Yes -
4 Support - Fu JM et al. (2022) Yes -
5 Support - Tian Meng et al. (2023) No -
6 Primary - Amélie Cordovado et al. (2025) No Autistic features, stereotypy, epilepsy/seizures
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1068C>T p.Ile356= synonymous_variant De novo - - 35982160 Fu JM et al. (2022)
c.1042C>T p.Arg348Cys missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.2862G>T p.Val954= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.433C>T p.Arg145Ter stop_gained De novo - Simplex 40226306 Amélie Cordovado et al. (2025)
c.2031_2032del p.Asp679GlnfsTer45 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.433C>T p.Arg145Ter stop_gained Familial Paternal Multiplex 36604604 Tian Meng et al. (2023)
c.658C>T p.Arg220Ter stop_gained Familial Maternal Multiplex 36604604 Tian Meng et al. (2023)
c.983G>A p.Trp328Ter stop_gained Familial Both parents Simplex 36604604 Tian Meng et al. (2023)
c.1178C>G p.Thr393Arg missense_variant De novo - Simplex 40226306 Amélie Cordovado et al. (2025)
c.1198G>C p.Glu400Gln missense_variant De novo - Simplex 40226306 Amélie Cordovado et al. (2025)
c.1655G>C p.Gly552Ala missense_variant De novo - Simplex 40226306 Amélie Cordovado et al. (2025)
c.2137C>G p.His713Asp missense_variant De novo - Simplex 40226306 Amélie Cordovado et al. (2025)
c.2701G>T p.Glu901Ter stop_gained Familial Maternal Simplex 40226306 Amélie Cordovado et al. (2025)
c.327+1G>T p.? splice_site_variant Familial Both parents Simplex 34764295 Francesca Mattioli et al. (2021)
c.799+1G>T p.? splice_site_variant Familial Both parents Multiplex 34764295 Francesca Mattioli et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

7/1/2025
3S

Initial score established: 3S

Krishnan Probability Score

Score 0.49593275079474

Ranking 2740/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99998063736174

Ranking 503/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94538565722578

Ranking 16449/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.2058242359676

Ranking 4179/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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