RASGRP2

Chr 11

RAS guanyl releasing protein 2

Also known as: CALDAG-GEFI, CDC25L

NCBI Gene: 10235 ENSG00000068831 UniProt: Q7LDG7

This brain-enriched nucleotide exchange factor activates small GTPases including RAS and RAP1 in response to calcium and diacylglycerol, and functions in platelet aggregation and immune cell adhesion through integrin activation. Biallelic mutations cause autosomal recessive bleeding disorder, platelet-type, 18, affecting platelet function. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.447).

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtBleeding disorder, platelet-type, 18

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · platelet-type bleeding disorder 18 · AR · ClinGen 2019

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.45

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.48Z-score

OE missense 0.78 (0.71–0.86)

294 obs / 374.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.13–0.45)

0≤0.351.4

Missense OE?0.78 (0.71–0.86)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 7 / 29.4Missense obs/exp: 294 / 374.9Syn Z: 0.45

Background carrier burden — how many people carry a rare variant somewhere in RASGRP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

785 rare PASS variants

Rare truncating (LoF)

1 in 1,500

108 rare PASS variants

Rare synonymous (reference)

1 in 130

351 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RASGRP2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 95	1 in 1,700
South Asian	~43k	1 in 64	1 in 2,000
Remaining (unassigned)	~30k	1 in 66	1 in 1,700
European (Finnish)	~27k	1 in 160	1 in 410
Admixed American	~22k	1 in 71	1 in 1,500
African / African American	~21k	1 in 71	1 in 2,400
East Asian	~20k	1 in 75	1 in 830
Ashkenazi Jewish	~13k	1 in 200	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 66	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.