This dissertation investigates the functional significance and therapeutic implications of novel extracellular domain (ECD) alterations in PDGFRA found in glioma. Specifically, this work presents a comprehensive assessment of the oncogenic potential and pharmacogenomic profiles of PDGFRA K385I/L, the defining alteration in myxoid glioneuronal tumor, and establishes a scalable framework for evaluating additional ECD mutations across diverse glioma subtypes. The dissertation further extends this approach to characterize twenty PDGFRA ECD variants identified in both pediatric and adult gliomas, revealing shared oncogenic properties and differential sensitivity to type II tyrosine kinase inhibitors. Finally, this work presents the discovery and real-time functional assessment of a novel MDM2::PDGFRA fusion in recurrent glioblastoma, highlighting translational strategies for integrating molecular characterization into patient care.