RAPGEF4

protein-coding

Rap guanine nucleotide exchange factor 4

Gene summary

Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in Rap protein signal transduction; regulation of neurotransmitter receptor localization to postsynaptic specialization membrane; and regulation of postsynapse organization. Predicted to act upstream of or within with a positive effect on hormone secretion. Predicted to act upstream of or within adenylate cyclase-activating G protein-coupled receptor signaling pathway; regulation of exocytosis; and secretion by cell. Located in cytosol. Implicated in autistic disorder. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_007023.4

Inheritance

ClinVar variants

U:129B:11

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr2:172,735,274-173,052,893

External References & Databases

Ensembl (ENSG00000091428)

Transcript & Mutation Effects

hg38 • Region Span ~317.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

prostate cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008315

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAPGEF4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 120

not providedTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007023.4. 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			3 clinvar	2 clinvar	4 clinvar	9
missense			123 clinvar	3 clinvar	2 clinvar	128
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	129	5	6	140

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007023.4	RefSeq	NP_008954.2	31	MANE Select
ENST00000397081.8	Ensembl	ENSP00000380271.3	31	MANE Select
NM_001100397.2	RefSeq	NP_001093867.1	28	Standard
NM_001282899.2	RefSeq	NP_001269828.1	27	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
cAMP signaling pathway - Homo sapiens (human)
Rap1 signaling pathway - Homo sapiens (human)
Phospholipase D signaling pathway - Homo sapiens (human)
Insulin secretion - Homo sapiens (human)

Biological Process

G protein-coupled receptor signaling pathway
small GTPase mediated signal transduction
calcium ion regulated exocytosis
regulation of exocytosis
cAMP-mediated signaling

Molecular Function

guanyl-nucleotide exchange factor activity
Ras guanyl-nucleotide exchange factor activity
protein binding
Ras GTPase binding
cAMP binding

Cellular Component

cytosol
plasma membrane
membrane
hippocampal mossy fiber to CA3 synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397081
Coding exons: 31
Length: 317620
Individuals with no LoFs: 124762
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 124796
p: 0.000136

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.83	447	570	0.784	0.0000318	6629
Missense (PolyPhen)		165	231.91	0.71149		2686
Synonymous	0.358	200	207	0.968	0.0000118	1894
Loss of Function	6.25	12	67.4	0.178	0.00000397	746

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00028	0.00028	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00023	0.00023	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide exchange factor (GEF) for RAP1A, RAP1B and RAP2A small GTPases that is activated by binding cAMP. Seems not to activate RAB3A. Involved in cAMP-dependent, PKA- independent exocytosis through interaction with RIMS2 (By similarity). {ECO:0000250, ECO:0000269|PubMed:10777494, ECO:0000269|PubMed:9856955}.;

Recessive Scores

pRec: 0.123

Intolerance Scores

LoFtool: 0.583
RVIS EVS: -0.77
RVIS percentile EVS: 13.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.844

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium