RAC3

Chr 17AD

Rac family small GTPase 3

NCBI Gene: 5881ENSG00000169750UniProt: P60763

The protein encoded by this gene is a GTPase which belongs to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with structural brain anomalies and dysmorphic faciesMIM #618577
AD
88
ClinVar variants
31
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— RAC3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 40 VUS of 88 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.27LOEUF
pLI 0.003
Z-score 1.06
OE 0.60 (0.31–1.27)
Tolerant

Highly tolerant — LoF variants common in population

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.
1.46Z-score
OE missense 0.63 (0.52–0.76)
78 obs / 123.8 exp
Tolerant

Mild missense constraint

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.0.60 (0.31–1.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.63 (0.52–0.76)
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.1.69
0≤1.21.6
LoF obs/exp: 5 / 8.3Missense obs/exp: 78 / 123.8Syn Z: -4.09

ClinVar Variant Classifications

88 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic10
VUS40
Likely Benign14
Benign1
Conflicting2
21
Pathogenic
10
Likely Pathogenic
40
VUS
14
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
20
0
21
Likely Pathogenic
0
7
3
0
10
VUS
1
29
9
1
40
Likely Benign
0
3
3
8
14
Benign
0
1
0
0
1
Conflicting
—2
Total14135988

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

View in ClinVar →

Protein Context — Lollipop Plot

RAC3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RAC3-related neurodevelopment disorder

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies

MIM #618577

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — RAC3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Radiomultiomics: quantitative CT clusters of severe asthma associated with multiomics.
Zounemat Kermani N et al.·Eur Respir J
2024
A p.N92K variant of the GTPase RAC3 disrupts cortical neuron migration and axon elongation.
Sugawara R et al.·J Biol Chem
2025
The p.R66W Variant in RAC3 Causes Severe Fetopathy Through Variant-Specific Mechanisms.
Sugawara R et al.·Cells
2024Functional
SETD8 inhibits apoptosis and ferroptosis of Ewing's sarcoma through YBX1/RAC3 axis.
Chen H et al.·Cell Death Dis
2024
Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants.
Priolo M et al.·Eur J Hum Genet
2023Review
A Pleiotropic and Functionally Divergent RAC3 Variant Disrupts Neurodevelopment and Impacts Organogenesis.
Sugawara R et al.·Cells
2025Functional
Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.
Scala M et al.·Brain
2022
Hypomethylated gene RAC3 induces cell proliferation and invasion by increasing FASN expression in endometrial cancer.
Meijuan C et al.·Int J Biochem Cell Biol
2022
Rac3 Expression and its Clinicopathological Significance in Patients With Bladder Cancer.
Chen M et al.·Pathol Oncol Res
2021Cohort
Gain-of-function p.F28S variant in RAC3 disrupts neuronal differentiation, migration and axonogenesis during cortical development, leading to neurodevelopmental disorder.
Nishikawa M et al.·J Med Genet
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Recurrent Breast CarcinomaStage III Breast Cancer AJCC v7Stage IIIA Breast Cancer AJCC v7

Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer

ACTIVE NOT RECRUITING
NCT02311933Phase PHASE2National Cancer Institute (NCI)Started 2015-05-28
Endoxifen HydrochlorideLaboratory Biomarker AnalysisPharmacological Study

External Resources

Links to major genomics databases and tools