Background: Limited and contradictory pharmacogenetic studies of NPHS2 gene R229Q polymorphism in nephrotic syndrome (NS) children and adults of different ethnicities steered us to investigate the genotype frequency and associated risk of this polymorphism in Middle East NS children and adults. Objectives: The present work aimed to study the effect of NPHS2 R229Q genetic variations on the susceptibility to idiopathic NS and the treatment response in NS children and adults from Assiut University and major Kuwait Hospitals. Patients and methods: A prospective observational cohort study was conducted which comprised a total of 100 idiopathic NS patients (30 children and 70 adults). Mutation analysis was carried out by Taqman allele discrimination of the NPHS2 gene R229Q polymorphism (rs61747728) using specific primers and probes. Results: The results indicate the presence of R229Q polymorphism in9% of our patients. Moreover, R229Q variant in Steroid-resistant nephrotic syndrome (SRNS) adults was observed in a single heterozygous form. A total of 100 patients were genotyped for the variant rs61747728. Ninety-one percent of patients carry the CC genotype (Homozygous), in addition only 9% were carriers of the CT genotype (Heterozygous), whereas no patients were carrying the TT genotype. The minor allele (T) frequency was 0.045, whereas the major allele (C) frequency was 0.955 in our population. Conclusion: NPHS2 p.R229Q plays an important role in enhancing the susceptibility of minimal change disease (MCD), focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome  (FSGS/SRNS), especially in Middle East population and age of late-onset patients. We recommend to screen for p.R229Q polymorphism in the diagnosis of SRNS among our population.