Human Gene Module / Chromosome 14 / RALGAPA1

RALGAPA1Ral GTPase activating protein catalytic subunit alpha 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 7
Rare Variants / Common Variants
12 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
14q13.2
Associated Disorders
-
Relevance to Autism

Whole exome sequencing of 75 Turkish patients diagnosed with ASD (based on DSM-5 criteria) identified a homozygous missense variant in the RALGAPA1 gene in a 10-year-old male presenting with ASD and developmental delay in Kayhan et al., 2026. Additional de novo variants in this gene, including a de novo loss-of-function variant and multiple de novo missense variants, have been reported in ASD probands from the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, and a Chinese ASD cohort (De Rubeis et al., 2014; Iossifov et al., 2014; Zhou et al., 2022; Fu et al., 2022; Yuan et al., 2023), while maternally-inherited loss-of-function variants in this gene were identified in two unrelated multiplex ASD families from the mAGRE cohort in Cirnigliaro et al., 2023.

Molecular Function

This gene encodes a major subunit of the RAL-GTPase activating protein. A similar protein in mouse binds E12, a transcriptional regulator of immunoglobulin genes. The mouse protein also functions in skeletal muscle by binding to the regulatory 14-3-3 proteins upon stimulation with insulin or muscle contraction. Biallelic variants in this gene are responsible for neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (NEDHRIT; OMIM 618797).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RALGAPA1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Fu JM et al. (2022) Yes -
5 Support - Yuan B et al. (2023) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
7 Primary - Gülsüm Kayhan et al. (2026) Yes DD
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.5387+1del - splice_site_variant De novo - - 36881370 Yuan B et al. (2023)
T>A p.Thr2381= synonymous_variant De novo - Simplex 35982160 Fu JM et al. (2022)
c.1174A>C p.Thr392Pro missense_variant De novo - Simplex 35982160 Fu JM et al. (2022)
c.2605C>T p.Arg869Cys missense_variant De novo - Simplex 35982160 Fu JM et al. (2022)
c.2434C>T p.Arg812Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5255A>C p.Asn1752Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.448A>T p.Met150Leu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3060C>T p.Ile1020= synonymous_variant De novo - Multiplex 35982160 Fu JM et al. (2022)
c.6823_6825del p.Leu2275del inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1493G>A p.Trp498Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4282C>T p.Arg1428Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1097C>G p.Ser366Cys missense_variant Familial Both parents - 41751633 Gülsüm Kayhan et al. (2026)
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.

4/1/2026
3

Initial score established: 3

Krishnan Probability Score

Score 0.49756983484149

Ranking 2363/25841 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 0.99999997807669

Ranking 157/18225 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 0.19615014662577

Ranking 109/18665 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 0.26752304623183

Ranking 3222/20870 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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