CNKSR2 encodes a multi-domain scaffolding protein that functions as a critical regulator of neuronal development and synaptic signaling. The protein contains multiple functional domains including SAM, CRIC, PDZ, and PH domains that facilitate protein-protein interactions 1. CNKSR2 localizes to the postsynaptic density of glutamatergic synapses where it serves as a scaffolding molecule connecting postsynaptic structural proteins like PSD95 2. The protein regulates MAPK cascade and small GTPase signaling pathways through interactions with molecules including RAF1, ARHGAP39, and CYTH2 1. CNKSR2 is essential for dendritic spine morphogenesis in hippocampal neurons, with its loss-of-function resulting in reduced PSD size and impaired hippocampal development affecting neuronal proliferation, migration, and synaptogenesis 2. Additionally, CNKSR2 acts as both a scaffold and activator of TNIK kinase during neuronal synapse development 3. Pathogenic variants in CNKSR2 cause Houge type X-linked syndromic intellectual developmental disorder (MRXSHG), characterized by intellectual disability, language delay, early-onset epilepsy, attention deficits, and hyperactivity 14. Most pathogenic variants are loss-of-function mutations including nonsense variants, deletions, and frameshift mutations 42. The disorder shows phenotypic variability even within families, and recent studies have expanded the clinical spectrum to include digital anomalies and hippocampal atrophy 2.