Exome-wide sequencing studies recently describedPTPN11as a novel brain somatic epilepsy gene. In contrast, germline mutations ofPTPN11are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of thePTPN11/KRAS/NF1genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e.,BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG withPTPN11alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains inNF1, KRAS,FGFR4andRHEB, as well asBRAFV600Ealterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG andPTPN11/KRAS/NF1alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with onlyBRAFV600Emutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations inPTPN11and otherRAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00401-023-02561-5.