RAC2

Chr 22ARAD

Rac family small GTPase 2

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

NCBI Gene: 5880ENSG00000128340UniProt: P15153

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]

Primary Disease Associations & Inheritance

?Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinemiaMIM #618987
AR
Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosisMIM #608203
AD
Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopeniaMIM #618986
AD
248
ClinVar variants
24
Pathogenic / LP
0.97
pLI score· haploinsufficient
1
Active trials
Clinical Summary— RAC2
⚡
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.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 80 VUS of 248 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.28LOEUF
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?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.
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?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.0.00 (0.00–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.34 (0.27–0.44)
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.1.08
0≤1.21.6
LoF obs/exp: 0 / 10.5Missense obs/exp: 42 / 122.8Syn Z: -0.45

ClinVar Variant Classifications

248 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic5
VUS80
Likely Benign118
Benign11
Conflicting3
19
Pathogenic
5
Likely Pathogenic
80
VUS
118
Likely Benign
11
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
17
0
19
Likely Pathogenic
0
4
1
0
5
VUS
3
64
12
1
80
Likely Benign
0
1
52
65
118
Benign
0
0
7
4
11
Conflicting
—3
Total3718970236

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

View in ClinVar →

Protein Context — Lollipop Plot

RAC2 · 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

?Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinemia

MIM #618987

Molecular basis of disorder known

Autosomal recessive

Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis

MIM #608203

Molecular basis of disorder known

Autosomal dominant

Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopenia

MIM #618986

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and functional spectrum of RAC2-related immunodeficiency.
Donkó Á et al.·Blood
2024Functional
RAC2 and primary human immune deficiencies.
Lougaris V et al.·J Leukoc Biol
2020Review
Radiomultiomics: quantitative CT clusters of severe asthma associated with multiomics.
Zounemat Kermani N et al.·Eur Respir J
2024
Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders.
Troeger A et al.·Exp Cell Res
2013Review
RAC2 GTPase deficiency and myeloid cell dysfunction in human and mouse.
Gu Y et al.·J Pediatr Hematol Oncol
2002Review
Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms.
Zhang P et al.·Nat Commun
2024
Not too little, not too much: the impact of mutation types in Wiskott-Aldrich syndrome and RAC2 patients.
Hsu AP·Clin Exp Immunol
2023Review
Allergic manifestations of actinopathies: A review.
Gard CN et al.·J Allergy Clin Immunol
2025Review
Integrated multi-omics reveals glycolytic gene signatures of lung adenocarcinoma brain metastasis and the impact of Rac2 lactylation on immunosuppressive microenvironment.
Yi Y et al.·J Transl Med
2025
RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation.
Doye A et al.·J Exp Med
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Case Report: Characterization of a RAC2 R68W homozygous activating mutation causing combined immune deficiency.
Desjardins A et al.·Front Immunol
2026🔓 Open AccessCase report
SIRT5-RAC2 Axis Drives Monocyte-to-Macrophage Differentiation to Promote Inflammatory Injury in Premature Ovarian Insufficiency.
TanTai W et al.·Adv Sci (Weinh)
2026
Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer.
Xi Y et al.·Cell Rep Med
2026🔓 Open AccessFunctional
Azathioprine ameliorates cellular senescence in rhabdomyolysis-induced acute kidney injury by inhibiting the Vav1/Rac2/NF-κB pathway in macrophages.
Su H et al.·Eur J Pharmacol
2026
C3G deregulation uncovers a dual role in B-cell lymphoma: tumor suppression and enhanced metastasis via Rap1 and Rac2 signaling.
Morán-Vaquero A et al.·Cell Commun Signal
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Breast Cancer

Treating Breast Cancer Patients Undergoing Trastuzumab Treatment With Carvedilol to Reduce Incidence of Heart Failure

ACTIVE NOT RECRUITING
NCT03879629Phase PHASE2Mayo ClinicStarted 2019-08-21
Carvedilol

External Resources

Links to major genomics databases and tools