Gliomas are the most prevalent neurological cancer in the USA and care modalities are not able to effectively combat these aggressive malignancies. Identifying new, more effective treatments require a deep understanding of the complex genetic variations and relevant pathway associations behind these cancers. Drawing connections between gene mutations with a responsive genetic target can help drive therapy selections to enhance patient survival. We have performed extensive molecular profiling of the Capicua gene (CIC), a tumor and transcriptional suppressor gene, and its mutation prevalence in reference to MAPK activation within clinical glioma tissue.CICmutations occur far more frequently in oligodendroglioma (52.1%) than in low-grade astrocytoma or glioblastoma.CIC-associated mutations were observed across all glioma subtypes, and MAPK-associated mutations were most prevalent inCICwild-type tissue regardless of the glioma subtype. MAPK activation, however, was enhanced inCIC-mutated oligodendroglioma. The totality of our observations reported supports the use ofCICas a relevant genetic marker for MAPK activation. Identification ofCICmutations, or lack thereof, can assist in selecting, implementing, and developing MEK/MAPK-inhibitory trials to improve patient outcomes potentially.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12032-023-02071-0.