RASGRP1

Chr 15

RAS guanyl releasing protein 1

Also known as: CALDAG-GEFI, CALDAG-GEFII, IMD64, RASGRP

NCBI Gene: 10125 ENSG00000172575 UniProt: O95267

This gene is a member of a family of genes characterized by the presence of a Ras superfamily guanine nucleotide exchange factor (GEF) domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. It activates the Erk/MAP kinase cascade and regulates T-cells and B-cells development, homeostasis and differentiation. Alternatively spliced transcript variants encoding different isoforms have been identified. Altered expression of the different isoforms of this protein may be a cause of susceptibility to systemic lupus erythematosus (SLE). [provided by RefSeq, Jul 2008]

Research

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtSystemic lupus erythematosus

UniProtImmunodeficiency 64 with lymphoproliferation

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · immunodeficiency 64 · AR · ClinGen 2025

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

0.32

LOEUF· LoF intol.

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Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.966

Z-score 4.95

OE 0.17 (0.10–0.32)

Highly constrained

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

Missense Constraint?

2.74Z-score

OE missense 0.62 (0.56–0.69)

259 obs / 416.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.32)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 7 / 41.3Missense obs/exp: 259 / 416.5Syn Z: 1.09

Background carrier burden — how many people carry a rare variant somewhere in RASGRP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 99

846 rare PASS variants

Rare truncating (LoF)

1 in 670

99 rare PASS variants

Rare synonymous (reference)

1 in 100

383 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RASGRP1. 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 110	1 in 530
South Asian	~43k	1 in 95	1 in 1,100
Remaining (unassigned)	~30k	1 in 120	1 in 590
European (Finnish)	~27k	1 in 270	1 in 1,900
Admixed American	~22k	1 in 98	1 in 3,600
African / African American	~21k	1 in 94	1 in 2,400
East Asian	~20k	1 in 89	1 in 2,800
Ashkenazi Jewish	~13k	1 in 250	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 100	≈ 1 in 1,200

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.

Exome coverage (gnomAD): 15 of 17 coding exons well covered in gnomAD exomes; exons 1, 4 marginal. Genomes: all 17.? see exons ↓