RAC3

Chr 17AD

Rac family small GTPase 3

NCBI Gene: 5881ENSG00000169750UniProt: P60763OMIM: 602050

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]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismADLOEUF 1.271 OMIM phenotype
Clinical Summary— RAC3
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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
9 unique Pathogenic / Likely Pathogenic· 33 VUS of 63 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 — RAC3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
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?
1.46Z-score
OE missense 0.63 (0.52–0.76)
78 obs / 123.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.60 (0.31–1.27)
0≤0.351.4
Missense OE?0.63 (0.52–0.76)
0≤0.61.4
Synonymous OE?1.69
0≤1.21.6
LoF obs/exp: 5 / 8.3Missense obs/exp: 78 / 123.8Syn Z: -4.09
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongRAC3-related neurodevelopment disorderOTHERAD

This gene — mechanism propensity

DN
0.81top 10%
GOF
0.75top 25%
LOF
0.3161th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. 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

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

GOFThe specific nucleotide substitution c.86C>T leading to p.(Pro29Leu) was shown in the C. elegans ortholog of RAC3 to result in aberrant axon guidance via an apparent gain-of-function mechanism.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

  1. 1.PMID 30293988 ↗

ClinVar Variant Classifications

63 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
Likely Pathogenic7
VUS33
Likely Benign14
Benign1
Conflicting2
2
Pathogenic
7
Likely Pathogenic
33
VUS
14
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
0
0
2
Likely Pathogenic
0
7
0
0
7
VUS
1
30
1
1
33
Likely Benign
0
3
3
8
14
Benign
0
1
0
0
1
Conflicting
—2
Total1434959

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap RAC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

RAC3 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients