RAPGEF2

Chr 4AD

Rap guanine nucleotide exchange factor 2

Also known as: CNrasGEF, NRAPGEP, PDZ-GEF1, PDZGEF1, RA-GEF, RA-GEF-1, RAGEF, Rap-GEP

NCBI Gene: 9693ENSG00000109756UniProt: Q9Y4G8

RAPGEF2 encodes a guanine nucleotide exchange factor that activates Rap and Ras family GTPases by promoting GDP-to-GTP exchange, serving as a critical link in intracellular signaling cascades and playing essential roles in neuronal migration, axon outgrowth, and formation of major brain commissures during development. Mutations cause familial adult myoclonic epilepsy with autosomal dominant inheritance, typically presenting in adulthood. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.197), indicating that complete loss of protein function is likely incompatible with normal development.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

?Epilepsy, familial adult myoclonic, 7MIM #618075
AD
0
Active trials
6
Pubs (1 yr)
37
P/LP submissions
0%
P/LP missense
0.20
LOEUF· LoF intol.
LOF
Mechanism· predicted
Clinical Summary— RAPGEF2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
37 unique Pathogenic / Likely Pathogenic· 136 VUS of 222 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.20LOEUF
pLI 1.000
Z-score 7.06
OE 0.11 (0.06–0.20)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
3.62Z-score
OE missense 0.65 (0.60–0.69)
532 obs / 824.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.11 (0.06–0.20)
0≤0.351.4
Missense OE0.65 (0.60–0.69)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 8 / 73.1Missense obs/exp: 532 / 824.3Syn Z: -0.38
DN
0.4487th %ile
GOF
0.5857th %ile
LOF
0.69top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.20

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

222 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic3
VUS136
Likely Benign13
Benign14
34
Pathogenic
3
Likely Pathogenic
136
VUS
13
Likely Benign
14
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
34
0
34
Likely Pathogenic
0
0
3
0
3
VUS
1
124
10
1
136
Likely Benign
0
3
0
10
13
Benign
0
0
7
7
14
Total11275418200

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RAPGEF2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Rare heterozygous de novo variants in RAPGEF2 are associated with a neurodevelopmental disorder.
Bereshneh AH et al.·Genet Med
2026
The guanine nucleotide exchange factor RapGEF2 is required for ERK-dependent immediate-early gene (Egr1) activation during fear memory formation.
Jiang SZ et al.·Cell Mol Life Sci
2024
Comprehensive Analysis of RAPGEF2 for Predicting Prognosis and Immunotherapy Response in Patients with Hepatocellular Carcinoma.
Wu Q et al.·J Oncol
2022Open AccessCohort
Cyclic AMP-dependent activation of ERK via GLP-1 receptor signalling requires the neuroendocrine cell-specific guanine nucleotide exchanger NCS-RapGEF2.
Xu W et al.·J Neuroendocrinol
2021
RAPGEF2 mediates oligomeric Aβ-induced synaptic loss and cognitive dysfunction in the 3xTg-AD mouse model of Alzheimer's disease.
Jang YN et al.·Neuropathol Appl Neurobiol
2021Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients