Using an antibody-based assay, we (i) identified an upstream variant at the UMOD locus with differential accessibility and transcription in human uromodulin-synthesizing kidney cell types and compartments that was strongly associated with circulating and urine uromodulin, CKD, and hypertension; (ii) placed the PRKAG2 locus in the same pathway as UMOD with respect to its disease associations; and (iii) showed that p.Cys466Arg in the uromodulin-glycosylating enzyme B4GALNT2 was a loss-of-function allele leading to higher serum uromodulin levels. The gene discussed is UMOD; the disease is hypertensive disorder.