Neurodevelopmental disorders (NDDs), such as intellectual disability (ID), can arise from genetic and environmental factors. PAK3, a gene crucial for brain development and synaptic plasticity, is involved in X-linked ID. Mutations in the PAK3 gene may also lead to autistic traits, epilepsy and other neurological symptoms. The most severe cases result from missense mutations in the kinase domain, rendering the protein stable but inactive.Our aim is to understand the specific effects of severe PAK3 variants on brain structure and function and assess the precise mechanism underlying severe PAK3-linked ID. We propose that the pathogenicity of PAK3 stable variants lacking kinase activity depends on a complex mechanism of signalling interference.We are focusing on the PAK3-G424R variant, associated with severe ID, microcephaly, epilepsy, and autistic traits. In vitro, PAK3-G424R lacks kinase activity, exhibits altered protein interactions, and maintains its stability. We generated the corresponding mouse model and are conducting in vitro analyses on other severe variants. To assess the specificity of the pathogenic mechanism underlying severe cases, we are comparing our results with the PAK3-R67C variant responsible for moderate ID in vitro and in vivo.The Pak3-G424R mouse model exhibits hyperactivity, stereotypies, cognitive defects, and secondary microcephaly, a more severe phenotype compared to that of the Pak3-R67C model. Electrophysiological recordings in the hippocampus reveal synaptic transmission abnormalities implicating pre and postsynaptic dysfunctions. Linking the observed deficits to biochemical alterations allowed us to put forward a new molecular mechanism wherein PAK3-G424R hinders the kinase activity of its partner PAK1.