RAPGEF4

Chr 2

Rap guanine nucleotide exchange factor 4

Also known as: CAMP-GEFII, CGEF2, EPAC, EPAC 2, EPAC2, Nbla00496

NCBI Gene: 11069 ENSG00000091428 UniProt: Q8WZA2 OMIM: 606058

Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in Ras 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. Predicted to be located in membrane. Predicted to be active in several cellular components, including glutamatergic synapse; hippocampal mossy fiber to CA3 synapse; and postsynaptic density. Implicated in autistic disorder. [provided by Alliance of Genome Resources, Apr 2025]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOEUF 0.29

Clinical Summary— RAPGEF4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 119 VUS of 151 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.992

Z-score 6.25

OE 0.18 (0.11–0.29)

Highly constrained

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

Missense Constraint?

1.83Z-score

OE missense 0.78 (0.72–0.85)

447 obs / 570.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.11–0.29)

0≤0.351.4

Missense OE?0.78 (0.72–0.85)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 12 / 67.4Missense obs/exp: 447 / 570.0Syn Z: 0.36

ClinVar Variant Classifications

151 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS119

Likely Benign5

Benign6

Pathogenic

119

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	119	0	0	119
Likely Benign	3	0	2	5
Benign	2	0	4	6
Total	124	1	6	131

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap RAPGEF4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →