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Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome, with an annual incidence of 24 cases per million among African-Americans and 5 per million among European-Americans in the United States. It ranks as the second most common glomerular disease in Europe and Latin America and the fifth in Asia. We conducted a case-control study involving 726 FSGS cases and 13,994 controls from diverse ethnic backgrounds, using panel sequencing of ∼2,500 podocyte-expressed genes. Rare variant association tests confirmed known risk genes (, ) and identified a significant association with the gene. The variant rs17047661, which encodes the Sl1/Sl2 (R1601G) allele, was previously linked to cerebral malaria protection and is now identified as a risk variant for FSGS. This highlights an evolutionary trade-off between infectious disease resistance and kidney disease susceptibility, emphasizing the role of adaptive immunity in FSGS pathogenesis and potential therapeutic targets.