NPHS2 encodes podocin, an integral membrane protein of the glomerular slit diaphragm that plays a critical role in regulating glomerular permeability 1. Podocin functions as a linker between the plasma membrane and the cytoskeleton, contributing to the structural integrity of the glomerular filtration barrier 2. NPHS2 is expressed in differentiated podocytes alongside other slit diaphragm proteins including nephrin, CD2AP, and synaptopodin 2. Mutations in NPHS2 are a significant cause of steroid-resistant nephrotic syndrome (SRNS), accounting for a substantial proportion of genetic cases, particularly in early-onset disease 3. NPHS2 mutations manifest in both familial and sporadic forms of SRNS and focal segmental glomerulosclerosis (FSGS) 1. The common R229Q variant shows population-specific associations, with increased FSGS risk in European-derived populations but not African-derived populations 1. Homozygous R229Q carriers have significantly elevated SRNS risk compared to non-carriers 4. Other pathogenic mutations including missense variants (P20L, P316S) and frameshift mutations (42delG) have been identified in SRNS patients 5. Recent organoid studies demonstrate that NPHS2 mutations result in reduced protein expression and abnormal NPHS1 localization, contributing to podocyte dysfunction 6. Molecular diagnosis of NPHS2 mutations enables accurate etiologic classification and personalized treatment strategies for SRNS patients.