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In genetic disease, an accurate expression landscape of disease genes and faithful animal models can facilitate genetic diagnoses and therapeutic advances respectively. Previously, we found that variants in NOS1AP, the gene that encodes nitric oxide synthase 1 adaptor protein, cause monogenic nephrotic syndrome. Here, we determine that an intergenic splice product of NOS1AP/Nos1ap and neighboring C1orf226/Gm7694, which prevents NOS1AP from binding to nitric oxide synthase 1, is the predominant isoform in mammalian kidney transcriptional and proteomic data. Gm7694 mice, whose allele exclusively disrupts the intergenic product, develop nephrotic syndrome phenotypes. In two male human subjects with nephrotic syndrome, we identify causative NOS1AP splice variants, including one predicted to abrogate intergenic splicing but initially misclassified as benign based on the canonical transcript. Finally, by modifying genetic background, we generate a faithful mouse model of NOS1AP-associated monogenic nephrotic syndrome that responds to anti-proteinuric treatment.