Human Gene Module / Chromosome 4 / RAPGEF2

RAPGEF2Rap guanine nucleotide exchange factor 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
8 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
4q32.1
Associated Disorders
-
Relevance to Autism

Bereshneh et al., 2026 identified five unrelated individuals carrying de novo heterozygous variants (three missense variants, a frameshift variant, and a nonsense variant) in the RAPGEF2 gene presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral abnormalities (including autism in two individuals), seizures, and dysmorphic features; functional assessment of the three missense variants and the nonsense variant in PDZ-GEF mutant Drosophila found that, while wild-type RAPGEF2 was able to rescue phenotypes associated with loss of PDZ (lethality, severe locomotion defects, aberrant microtubular stability in motor neurons axons, and synaptic overgrowth at neuromuscular junctions in third instar larvae), mutant RAPGEF2 with these variants failed to do so, indicating a loss-of-function effect. De novo missense variants in the RAPGEF2 gene have been previously reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort (De Rubeis et al., 2014; Yuen et al., 2017; Zhou et al., 2022).

Molecular Function

Members of the RAS subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF2, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RAPGEF2 (5 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 Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support - Nariko Arimura et al. (2020) No -
4 Support - Zhou X et al. (2022) Yes -
5 Primary - Ali H Bereshneh et al. () No ASD, ADHD, epilepsy/seizures
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3634C>T p.Arg1212Ter stop_gained De novo - - 41556274 Ali H Bereshneh et al. ()
c.433C>G p.Arg145Gly missense_variant De novo - - 41556274 Ali H Bereshneh et al. ()
c.758T>C p.Met253Thr missense_variant De novo - - 41556274 Ali H Bereshneh et al. ()
c.3154C>G p.Leu1052Val missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3332G>T p.Gly1111Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.454_455delinsAG p.Val152Arg missense_variant De novo - - 41556274 Ali H Bereshneh et al. ()
c.3305C>G p.Ala1102Gly missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1769dup p.Leu590PhefsTer15 frameshift_variant De novo - Simplex 41556274 Ali H Bereshneh et al. ()
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 0.56905761996544

Ranking 1064/25841 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 0.99999666674105

Ranking 374/18225 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 0.71884269029956

Ranking 1286/18665 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 0.40949908673373

Ranking 1351/20870 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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