Optic nerve gliomas (ONGs) in children are uniformly low-grade gliomas that frequently cause vision loss. Optic nerve gliomas in adults are reported to be more clinically aggressive with frequent transformation into high-grade gliomas. We report a child with sporadic ONG and an aggressive clinical course. Tumor molecular characterization identified KIAA1549-BRAF fusion but also set domain-containing protein 2 (SETD2; OMIM, 612778) mutation, previously reported only, to our knowledge, in high-grade gliomas and non–central nervous system cancers.