RAPGEF3
protein-codingRap guanine nucleotide exchange factor 3
Gene summary
Enables guanyl-nucleotide exchange factor activity and protein domain specific binding activity. Involved in several processes, including Rap protein signal transduction; cellular response to cAMP; and regulation of syncytium formation by plasma membrane fusion. Located in several cellular components, including filopodium; lamellipodium; and microvillus. Implicated in nicotine dependence. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Jul 2025]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~36.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RAPGEF3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001098531.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 3 | 3 | 7 | ||
| missense | 145 | 6 | 3 | 154 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 9 | 9 | ||||
| Total | 0 | 0 | 156 | 9 | 6 | 171 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001092001.2 | 28 | MANE Select | |
| Ensembl | ENSP00000395708.2 | 28 | MANE Select | |
| RefSeq | NP_001092002.1 | 27 | Standard | |
| RefSeq | NP_006096.2 | 27 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Long-term potentiation - Homo sapiens (human)
- Serotonergic synapse - Homo sapiens (human)
- Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
- cAMP signaling pathway - Homo sapiens (human)
- Rap1 signaling pathway - Homo sapiens (human)
Biological Process
- angiogenesis
- signal transduction
- cell population proliferation
- cAMP-mediated signaling
- Rap protein signal transduction
Molecular Function
- guanyl-nucleotide exchange factor activity
- protein binding
- Rap guanyl-nucleotide exchange factor activity
- protein domain specific binding
- cAMP binding
Cellular Component
- plasma membrane
- microvillus
- endomembrane system
- membrane
- lamellipodium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000449771
- Coding exons
- 28
- Length
- 36369
- Individuals with no LoFs
- 125617
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 131
- Defined
- 125748
- p
- 0.000521
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.867 | 498 | 555 | 0.897 | 0.0000343 | 5904 |
| Missense (PolyPhen) | 146 | 177.24 | 0.82374 | 1850 | ||
| Synonymous | 0.495 | 217 | 226 | 0.958 | 0.0000135 | 1885 |
| Loss of Function | 1.85 | 43 | 58.3 | 0.738 | 0.00000350 | 566 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00065 | 0.00062 | rare |
| Latino/Admixed American | 0.00050 | 0.00049 | rare |
| Ashkenazi Jewish | 0.00021 | 0.00020 | rare |
| East Asian | 0.00060 | 0.00060 | rare |
| Finnish | 0.00015 | 0.00014 | rare |
| European (Non-Finnish) | 0.00044 | 0.00043 | rare |
| South Asian | 0.0012 | 0.0012 | notable |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Guanine nucleotide exchange factor (GEF) for RAP1A and RAP2A small GTPases that is activated by binding cAMP. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which it activates the PI3K gamma complex and which is involved in angiogenesis. Plays a role in the modulation of the cAMP-induced dynamic control of endothelial barrier function through a pathway that is independent on Rho- mediated signaling. Required for the actin rearrangement at cell- cell junctions, such as stress fibers and junctional actin. {ECO:0000269|PubMed:10777494, ECO:0000269|PubMed:21840392, ECO:0000269|PubMed:9853756}.;
Recessive Scores
- pRec
- 0.211
Intolerance Scores
- LoFtool
- 0.770
- RVIS EVS
- -0.28
- RVIS percentile EVS
- 33.59
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.929
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |