KALRN encodes kalirin, a multidomain guanine nucleotide exchange factor (GEF) that activates Rho family GTPases to regulate neuronal morphology and synaptic function 1. Kalirin promotes neurite outgrowth, dendritic spine formation and remodeling, and regulates the actin cytoskeleton through its GEF activity 2. The protein functions as a central regulator of synaptic plasticity and is expressed in multiple isoforms generated by alternative splicing, particularly in the brain where exon 37 inclusion modulates neuronal function 1. KALRN dysregulation is implicated in diverse neuropsychiatric and neurodegenerative disorders. Genetic studies link KALRN variants to autism spectrum disorder, Alzheimer's disease, schizophrenia, intellectual disability, and ischemic stroke 23. A rare D1338N variant impairs Rac1 activation and correlates with reduced cortical thickness in schizophrenia and depression patients 4. KALRN also emerges as a TDP-43 splicing target; cryptic splicing following TDP-43 loss causes KALRN downregulation and neuronal dysfunction in frontotemporal dementia and ALS 5. Additionally, KALRN gene polymorphisms associate with coronary artery disease risk in type 2 diabetic patients 67. KALRN represents a promising therapeutic target for synaptopathies and neurodegenerative diseases 2.