CDC42

Chr 1AD

cell division cycle 42

Also known as: CDC42Hs, G25K, TKS

NCBI Gene: 998 ENSG00000070831 UniProt: P60953 OMIM: 116952

CDC42 encodes a small GTPase that regulates actin cytoskeleton dynamics, cell migration, and neuronal processes including dendritic spine formation and filopodia extension. Mutations cause Takenouchi-Kosaki syndrome, a neurodevelopmental disorder with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.501), reflecting its essential role in cellular functions.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression. This protein is highly similar to Saccharomyces cerevisiae Cdc 42, and is able to complement the yeast cdc42-1 mutant. The product of oncogene Dbl was reported to specifically catalyze the dissociation of GDP from this protein. This protein could regulate actin polymerization through its direct binding to Neural Wiskott-Aldrich syndrome protein (N-WASP), which subsequently activates Arp2/3 complex. Alternative splicing of this gene results in multiple transcript variants. Pseudogenes of this gene have been identified on chromosomes 3, 4, 5, 7, 8 and 20. [provided by RefSeq, Apr 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.501 OMIM phenotype

Clinical Summary— CDC42

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Gene-Disease Validity (ClinGen)

macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.79) — some intolerance to loss-of-function variants.

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ClinVar Variants

22 unique Pathogenic / Likely Pathogenic· 42 VUS of 156 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 — CDC42

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.787

Z-score 2.55

OE 0.11 (0.04–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.04Z-score

OE missense 0.16 (0.11–0.24)

17 obs / 104.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.11 (0.04–0.50)

0≤0.351.4

Missense OE?0.16 (0.11–0.24)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 1 / 9.5Missense obs/exp: 17 / 104.3Syn Z: -0.61

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCDC42-related neurodevelopmental disorderOTHERAD

This gene — mechanism propensity

0.6161th %ile

GOF

0.74top 25%

LOF

0.61top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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 · 95% of P/LP are missense

DNprediction above median · 1 literature citation

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

DNHere, we expressed wild-type cdc42, a constitutively active cdc42 mutant (cdc42F28L) and a dominant negative cdc42 mutant (cdc42N17), respectively, in the primary hippocampal neurons to alter the activity of cdc42. We found that cdc42 activities were paralleled with the capacities to promote axonoge1

GOFMutants differentially perturb polarized migration, with CDC42Ser83Pro and CDC42Ala159Val overexpression variably enhancing the wound closure ability of transfected cells compared to the wild-type protein, whereas CDC42Tyr23Cys, CDC42Arg68Gln, and CDC42Glu171Lys fail to do that, supporting a gain-of2

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

156 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic13

VUS42

Likely Benign63

Benign12

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	9	0	0	9
Likely Pathogenic	1	12	0	0	13
VUS	7	30	4	1	42
Likely Benign	0	0	30	33	63
Benign	0	0	9	3	12
Conflicting	—				1
Total	8	51	43	37	140

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap CDC42 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →