RAC2

Chr 22ARAD

Rac family small GTPase 2

Also known as: EN-7, Gx, HSPC022, IMD73A, IMD73B, IMD73C, p21-Rac2

NCBI Gene: 5880 ENSG00000128340 UniProt: P15153 OMIM: 602049

The protein is a plasma membrane-associated small GTPase that regulates neutrophil functions including chemotaxis, phagocytosis, and superoxide production through the NADPH oxidase complex. Mutations cause primary immunodeficiencies with defective neutrophil chemotaxis and variable presentations including hypogammaglobulinemia, leukocytosis, or lymphopenia, inherited in autosomal recessive or autosomal dominant patterns. The gene is highly constrained against loss-of-function mutations, indicating its critical importance for cellular function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 0.283 OMIM phenotypes

Clinical Summary— RAC2

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Gene-Disease Validity (ClinGen)

immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia · ARModerate

Moderate evidence — consider for supplementary testing

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

24 unique Pathogenic / Likely Pathogenic· 80 VUS of 248 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — RAC2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.28LOEUF

pLI 0.966

Z-score 3.01

OE 0.00 (0.00–0.28)

Highly constrained

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

Missense Constraint

2.59Z-score

OE missense 0.34 (0.27–0.44)

42 obs / 122.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.28)

0≤0.351.4

Missense OE0.34 (0.27–0.44)

0≤0.61.4

Synonymous OE1.08

0≤1.21.6

LoF obs/exp: 0 / 10.5Missense obs/exp: 42 / 122.8Syn Z: -0.45

0.5967th %ile

GOF

0.6248th %ile

LOF

0.63top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.28

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNDominant negative mutation of the hematopoietic-specific Rho GTPase, Rac 2, is associated with a human phagocyte immunodeficiency.PMID:10961859

GOFAt the adjacent amino acid, there is variation reported in somatic mutation databases6 and a single report of a constitutional p.(Glu62Lys) change in RAC2 that resulted in a gain of functionPMID:30293988

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.