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
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
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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.

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