With LOF mutations in the CDK4/6 binding partner CCND2 causing microcephaly (Pirozzi et al. 2021), and GOF CCND2 mutations leading to brain overgrowth (Mirzaa et al. 2014), we conclude that CDK4 and G1 Cyclin–CDK activity represents a key axis controlling human brain growth. The gene discussed is PCNA; the disease is microcephaly.