Human Gene Module / Chromosome 7 / CAPZA2

CAPZA2capping actin protein of muscle Z-line subunit alpha 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
1 / 3
Rare Variants / Common Variants
3 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
7q31.2
Associated Disorders
-
Relevance to Autism

Hellman et al., 2024 reported a p.Arg295Leu missense variant in the CAPZA2 gene in a proband diagnosed with autism and presenting with developmental delay and intellectual disability; this missense variant had been previously reported in a proband presenting with developmental delay and a history of seizures in Huang et al., 2020. Guo et al., 2025 subsequently found that CAPZA2 heterozygous knockout mice demonstrated reduced expression in the hippocampus and prefrontal cortex, as well as exhibited motor dysfunction and anxiety-like behaviors, impairments in spatial and non-spatial memory, and deficits in social interactions; these phenotypes were mirrored in mice heterozygous for the human-specific Arg259Leu missense variant previously reported in Huang et al., 2020 and Hellman et al., 2024. Huang et al., 2020 also reported a proband with a p.Lys256Glu missense variant who was diagnosed with autism and presented with developmental delay and intellectual disability; functional studies of this variant in Drosophila demonstrated a reduced ability to rescue the lethality phenotype in flies that were null for cpa (the CAPZA orthologue in Drosophila), consistent with a partial loss-of-function effect.

Molecular Function

The protein encoded by this gene is a member of the F-actin capping protein alpha subunit family. It is the alpha subunit of the barbed-end actin binding protein Cap Z. By capping the barbed end of actin filaments, Cap Z regulates the growth of the actin filaments at the barbed end.

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Reports related to CAPZA2 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Yan Huang et al. (2020) No ASD, ID, epilepsy/seizures
2 Primary - Jadin M Heilmann et al. (2024) Yes -
3 Recent Recommendation - Mei Guo et al. (2025) No ASD
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.766A>G p.Lys256Glu missense_variant De novo - Simplex 32338762 Yan Huang et al. (2020)
c.776G>T p.Arg259Leu missense_variant De novo - Simplex 32338762 Yan Huang et al. (2020)
c.776G>T p.Arg259Leu missense_variant Unknown Not maternal - 39908527 Jadin M Heilmann et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

10/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.49722938526561

Ranking 2428/25841 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 0.98660582064403

Ranking 1940/18225 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 0.91317492401381

Ranking 7974/18665 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 0.22772422367961

Ranking 3818/20870 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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