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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 48 VUS of 109 total submissions

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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 →

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GeneReview available — RAC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.15 (0.06–0.47)

0≤0.351.4

Missense OE?0.20 (0.14–0.28)

0≤0.61.4

Synonymous OE?0.83

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

This gene — mechanism propensity

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 · 100% of P/LP are missense

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 cerebella1

GOFNotably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas.2

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

109 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic19

VUS48

Likely Benign15

Benign6

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	8	0	0	8
Likely Pathogenic	0	19	0	0	19
VUS	10	31	6	1	48
Likely Benign	1	1	5	8	15
Benign	0	0	3	3	6
Conflicting	—				1
Total	11	59	14	12	97

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 61) ClinVar copy-number / structural variants overlap RAC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →