CDC42

Chr 1AD

cell division cycle 42

Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase (PubMed:15642749). Regulates cell migration (PubMed:17038317, PubMed:22843693). In neurons, plays a role in the extension and maintenance of the formation of filopodia, thin and actin-rich surface projections (PubMed:14978216). Required for DOCK10-mediated spine formation in Purkinje cells and hippocampal neurons. In podocytes, facilitates filopodia and podosomes formation upon DOCK11-activation (PubMed:33523862). Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Also plays a role in phagocytosis through organization of the F-actin cytoskeleton associated with forming phagocytic cups (PubMed:26465210). Upon activation by PLEKHG4B, involved in actin cytoskeletal remodeling during epithelial cell-cell junction formation (PubMed:33310911)

Primary Disease Associations & Inheritance

Takenouchi-Kosaki syndromeMIM #616737

ClinVar variants

Pathogenic / LP

0.79

pLI score

Active trials

Clinical Summary— CDC42

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Population Constraint (gnomAD)

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

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Clinical Trials

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

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?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.

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?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.0.11 (0.04–0.50)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.16 (0.11–0.24)

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.1.12

0≤1.21.6

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