Pharmacologic inhibition and exon 4-specific perturbation of <i>CLK1</i> reduced tumor cell viability and disrupted cancer-relevant splicing and transcriptional programs.<h4>Conclusions</h4>This study systematically characterizes splicing in pediatric brain tumors, identifies splicing-informed subgroups, and prioritizes <i>CLK1</i> exon 4 as an oncofetal tumor-specific event, motivating further preclinical exploration. Here, CLK1 is linked to brain neoplasm.