Variants in the phosphoprotein phosphatase-2 regulatory protein-5D gene ( PPP2R5D ) cause the clinical phenotype of Jordan's Syndrome (PPP2R5D-related disorder), which includes intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder and delayed motor skill development. The disorder originates from de novo single nucleotide mutations, generating missense variants that act in a dominant manner. Pathogenic mutations altering 13 different amino acids have been identified, with the E198K variant accounting for ∼40% of reported cases. Here, we use CRISPR-PRIME genomic editing to introduce a transition (c.592G>A) in the PPP2R5D allele in a heterozygous manner in HEK293 cells, generating E198K-heterozygous lines to complement existing E420K variant lines. We generate global protein and phosphorylation profiles of wild-type, E198K, and E420K cell lines and find unique and shared changes between variants and wild-type cells in kinase- and phosphatase-controlled signaling cascades. As shared signaling alterations, we observed ribosomal protein S6 (RPS6) hyperphosphorylation, indicative of increased ribosomal protein S6-kinase activity. Rapamycin treatment suppressed RPS6 phosphorylation in both, suggesting activation of mTORC1. Intriguingly, our data suggest AKT-dependent (E420K) and -independent (E198K) activation of mTORC1. Thus, although upstream activation of mTORC1 differs between PPP2R5D-related disorder genotypes, treatment with rapamycin or a p70S6K inhibitor warrants further investigation as potential therapeutic strategies for patients.