RAC1

Chr 7AD

Rac family small GTPase 1

Also known as: MIG5, MRD48, Rac-1, TC-25, p21-Rac1

NCBI Gene: 5879 ENSG00000136238 UniProt: P63000 OMIM: 602048

RAC1 encodes a plasma membrane-associated small GTPase that regulates diverse cellular processes including cytoskeletal reorganization, cell migration, neuronal adhesion and differentiation, dendritic spine formation, and synaptic plasticity. Mutations cause autosomal dominant intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI 0.76, LOEUF 0.47), suggesting that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.471 OMIM phenotype

Clinical Summary— RAC1

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.76) — some intolerance to loss-of-function variants.

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.47LOEUF

pLI 0.762

Z-score 2.90

OE 0.15 (0.06–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.13Z-score

OE missense 0.20 (0.14–0.28)

24 obs / 121.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.15 (0.06–0.47)

0≤0.351.4

Missense OE0.20 (0.14–0.28)

0≤0.61.4

Synonymous OE0.83

0≤1.21.6

LoF obs/exp: 2 / 13.5Missense obs/exp: 24 / 121.1Syn Z: 0.96

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongRAC1-related neurodevelopmental disorderOTHERAD

0.6162th %ile

GOF

0.6443th %ile

LOF

0.62top 25%

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

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

LOFLOEUF 0.47

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellaPMID:28886345

GOFNotably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas.PMID:22842228

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