Ependymomas encompass multiple, clinically relevant tumor types based on localization, genetic alterations, and epigenetic and transcriptomic profiles. Tumors belonging to the methylation class of spinal ependymoma (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, molecular data of SP-EPN are scarce, and clear treatment recommendations are lacking. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations. Yet, it remains unclear whether SP-EPN with germline or sporadic NF2 mutations or with NF2 wild type status differ clinically or molecularly. To provide a comprehensive molecular profile of SP-EPN, we integrated epigenetic, genomic, transcriptomic, and histological analyses of up to 237 cases. Clustering of methylation data revealed two distinct molecular SP-EPN subtypes. The distribution of NF2 mutated cases differed significantly across these subtypes (p