RASGRP2

Chr 11AR

RAS guanyl releasing protein 2

Also known as: CALDAG-GEFI, CDC25L

NCBI Gene: 10235ENSG00000068831UniProt: Q7LDG7

The protein encoded by this gene is a brain-enriched nucleotide exchanged factor that contains an N-terminal GEF domain, 2 tandem repeats of EF-hand calcium-binding motifs, and a C-terminal diacylglycerol/phorbol ester-binding domain. This protein can activate small GTPases, including RAS and RAP1/RAS3. The nucleotide exchange activity of this protein can be stimulated by calcium and diacylglycerol. Four alternatively spliced transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

?Bleeding disorder, platelet-type, 18MIM #615888
AR
333
ClinVar variants
39
Pathogenic / LP
0.24
pLI score
0
Active trials
Clinical Summary— RASGRP2
🧬
Gene-Disease Validity (ClinGen)
platelet-type bleeding disorder 18 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
39 Pathogenic / Likely Pathogenic· 120 VUS of 333 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.45LOEUF
pLI 0.244
Z-score 3.83
OE 0.24 (0.13–0.45)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.48Z-score
OE missense 0.78 (0.71–0.86)
294 obs / 374.9 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.0.24 (0.13–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.71–0.86)
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.0.95
0≤1.21.6
LoF obs/exp: 7 / 29.4Missense obs/exp: 294 / 374.9Syn Z: 0.45

ClinVar Variant Classifications

333 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic19
VUS120
Likely Benign127
Benign38
Conflicting9
20
Pathogenic
19
Likely Pathogenic
120
VUS
127
Likely Benign
38
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
2
11
0
20
Likely Pathogenic
6
9
4
0
19
VUS
0
107
12
1
120
Likely Benign
0
5
54
68
127
Benign
0
0
33
5
38
Conflicting
—9
Total1312311474333

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

View in ClinVar →

Protein Context — Lollipop Plot

RASGRP2 · 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

?Bleeding disorder, platelet-type, 18

MIM #615888

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Memory B Cells Activate Brain-Homing, Autoreactive CD4(+) T Cells in Multiple Sclerosis.
Jelcic I et al.·Cell
2018
RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology.
Canault M et al.·Int J Mol Sci
2020Review
RASGRP2 is a potential immune-related biomarker and regulates mitochondrial-dependent apoptosis in lung adenocarcinoma.
Liu Y et al.·Front Immunol
2023
Molecular Pathogenesis of Inherited Platelet Dysfunction.
Rodríguez-Alén A et al.·Biomolecules
2025Review
Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding.
Westbury SK et al.·Blood
2017
RASGRP2 gene variations associated with platelet dysfunction and bleeding.
Palma-Barqueros V et al.·Platelets
2019
[Expression of RASGRP2 in Lung Adenocarcinoma and Its Effect 
on Immune Microenvironment].
Zhao S et al.·Zhongguo Fei Ai Za Zhi
2021
[The clinical characteristics and molecular pathogenesis of a variant Glanzmann's thrombasthenia-like pedigree].
Lyu SJ et al.·Zhonghua Xue Ye Xue Za Zhi
2018
Novel variants in FERMT3 and RASGRP2-Genetic linkage in Glanzmann-like bleeding disorders.
Manukjan G et al.·Pediatr Blood Cancer
2020Case report
A novel missense variant in the RASGRP2 gene in patients with moderate to severe bleeding disorder.
Alharby E et al.·Platelets
2020Cohort
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