RAPGEF6

Chr 5

Rap guanine nucleotide exchange factor 6

Also known as: KIA001LB, PDZ-GEF2, PDZGEF2, RA-GEF-2, RAGEF2

NCBI Gene: 51735ENSG00000158987UniProt: Q8TEU7

Enables several functions, including GTP-dependent protein binding activity; guanyl-nucleotide exchange factor activity; and phosphatidic acid binding activity. Involved in microvillus assembly; positive regulation of GTPase activity; and protein localization to plasma membrane. Located in several cellular components, including apical plasma membrane; centrosome; and endocytic vesicle. [provided by Alliance of Genome Resources, Jul 2025]

225
ClinVar variants
17
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RAPGEF6
⚡
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
17 Pathogenic / Likely Pathogenic· 197 VUS of 225 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.28LOEUF
pLI 0.996
Z-score 6.74
OE 0.18 (0.12–0.28)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.56Z-score
OE missense 0.85 (0.80–0.90)
723 obs / 850.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.18 (0.12–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.80–0.90)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 14 / 78.3Missense obs/exp: 723 / 850.9Syn Z: -0.76

ClinVar Variant Classifications

225 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic2
VUS197
Likely Benign6
Benign5
15
Pathogenic
2
Likely Pathogenic
197
VUS
6
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
15
0
15
Likely Pathogenic
0
0
2
0
2
VUS
0
188
9
0
197
Likely Benign
0
3
2
1
6
Benign
0
1
1
3
5
Total0192294225

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

View in ClinVar →

Protein Context — Lollipop Plot

RAPGEF6 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
miR-342-5p as a Potential Regulator of HER2 Breast Cancer Cell Growth.
Lindholm EM et al.·Microrna
2019
Alternative Splicing Changes Promoted by NOVA2 Upregulation in Endothelial Cells and Relevance for Gastric Cancer.
Di Matteo A et al.·Int J Mol Sci
2023
A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs.
Hadji Rasouliha S et al.·PLoS Genet
2019
Exploring genetic and immune cell dynamics in systemic lupus erythematosus patients with Epstein-Barr virus infection via machine learning.
Gui J et al.·Rheumatology (Oxford)
2025Cohort
Targeted RNA sequencing in the routine clinical detection of fusion genes in salivary gland tumors.
Bubola J et al.·Genes Chromosomes Cancer
2021
Weighted gene co-expression network analysis and drug-gene interaction bioinformatics uncover key genes associated with various presentations of malaria infection in African children and major drug candidates.
Nambou K et al.·Infect Genet Evol
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools