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

This gene encodes a member of the Ras superfamily of small guanosine triphosphate (GTP)-metabolizing proteins. The encoded protein localizes to the plasma membrane, where it regulates diverse processes, such as secretion, phagocytosis, and cell polarization. Activity of this protein is also involved in the generation of reactive oxygen species. Mutations in this gene are associated with neutrophil immunodeficiency syndrome. There is a pseudogene for this gene on chromosome 6. [provided by RefSeq, Jul 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

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

7 unique Pathogenic / Likely Pathogenic· 77 VUS of 227 total submissions

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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 OE?0.00 (0.00–0.28)

0≤0.351.4

Missense OE?0.34 (0.27–0.44)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

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

This gene — mechanism propensity

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.1

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 function2

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

References

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic4

VUS77

Likely Benign118

Benign11

Conflicting2

Pathogenic

Likely Pathogenic

VUS

118

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	0	4	0	0	4
VUS	4	64	8	1	77
Likely Benign	0	1	52	65	118
Benign	0	0	7	4	11
Conflicting	—				2
Total	5	71	67	70	215

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap RAC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →