Human Gene Module / Chromosome 4 / GABRA2

GABRA2gamma-aminobutyric acid type A receptor subunit alpha2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
13 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
4p12
Associated Disorders
-
Relevance to Autism

Heterozygous variants in GABRA2 are responsible for developmental and epileptic encephalopathy 78 (DDE78; OMIM 618557). Adamo-Croux et al., 2025 reported six new patients with GABRA2 variants identified through a French national collaboration; all six individuals presented with epilepsy and developmental delay, and four were reported to present with autism spectrum disorder. Maljevic et al., 2019 had previously identified a DDE78 patient with ASD and a de novo GABRA2 missense variant, as well as two siblings with an attenuated form of DEE78 caused by a mosaic paternally-inherited missense variant (the proband was diagnosed with ASD, while his sister did not have autistic features); functional analysis in Xenopus oocytes demonstrated that both of these ASD-associated missense variants resulted in a loss-of-function effect. Several de novo missense variants in this gene have been identified in ASD probands, including a missense variant that was absent in ExAC and gnomAD and predicted to be damaging by CADD, REVEL, and MPC in a SPARK proband (Takata et al., 2018; Zhou et al., 2022; Fu et al., 2022). Gabra2 interacts with collybistin, the protein encoded by the ARHGEF9 gene (Hines et al., 2018). Hines et al., 2022 found that mutating the collybistin-binding motif within the large intracellular loop of Gabra2 and replacing it with the binding motif for gephyrin from Gabra1 (Gabra2-1) resulted in strongly downregulated collybistin expression in addition to deficits in working and recognition memory, hyperactivity, anxiety, and reduced social preference, recapitulating the frequently reported features of patients with ARHGEF9 mutations.

Molecular Function

Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interfaces. When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient. Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser
Reports related to GABRA2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
2 Support - Rochelle M Hines et al. (2018) No -
3 Support - Snezana Maljevic et al. (2019) No ASD, ID
4 Support - Hines DJ et al. (2022) No -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Fu JM et al. (2022) Yes -
7 Primary - Marie Adamo-Croux et al. () No ASD
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1127C>T p.Pro376Leu missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.829G>A p.Glu277Lys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.788T>C p.Met263Thr missense_variant De novo - - 31032849 Snezana Maljevic et al. (2019)
c.851T>C p.Val284Ala missense_variant De novo - - 31032849 Snezana Maljevic et al. (2019)
c.871C>G p.Leu291Val missense_variant De novo - - 31032849 Snezana Maljevic et al. (2019)
c.626C>T p.Ala209Val missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.799C>G p.Leu267Val missense_variant De novo - Simplex 40528577 Marie Adamo-Croux et al. ()
c.851T>C p.Val284Ala missense_variant De novo - Simplex 40528577 Marie Adamo-Croux et al. ()
c.910C>G p.Leu304Val missense_variant De novo - Simplex 40528577 Marie Adamo-Croux et al. ()
c.943T>C p.Trp315Arg missense_variant De novo - Simplex 40528577 Marie Adamo-Croux et al. ()
c.862A>G p.Thr288Ala missense_variant Unknown Not maternal - 40528577 Marie Adamo-Croux et al. ()
c.690del p.Lys231AsnfsTer9 frameshift_variant Unknown Not maternal - 40528577 Marie Adamo-Croux et al. ()
c.975C>A p.Phe325Leu missense_variant Familial Paternal Multiplex 31032849 Snezana Maljevic et al. (2019)
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 0.61241812595679

Ranking 171/25841 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 0.97696370138233

Ranking 2211/18225 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 0.92717370764627

Ranking 10608/18665 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 -0.013124605432105

Ranking 9095/20870 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
Submit New Gene

Report an Error