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Hypertension is a leading risk factor for cardiovascular events and considered as a complex genetic disease. Previous studies have revealed many common variants relevant to hypertension. However, the contributions of rare variants and the underlying mechanisms are still poorly understood. Through a case-control study with whole-exome sequencing, we found that rare nonsynonymous variants in GUCY1A3 gene were enriched in the patients with early-onset hypertension. To assess the effects of rare variants of GUCY1A3 , a knock-in mouse model carrying a variant corresponding to Pro637His in human GUCY1A3 was generated, and the blood pressure (BP) was measured by telemetry.The baseline systolic BP of both homozygous (P637H +/+ ) and heterozygous (P637H + )mice were higher than their wide-type (WT) littermate controls. After administration of eNOS inhibitor, BP elevated in all genotypes, and the P637H +/+ and P637H + mice had profoundly higher BP than WT. The vascular dysfunction in mutated mice was determined as contraction curves of aorta ring elevated earlier and higher, and relaxation curves decreased later than WT rings. Furthermore, compared to WT mice, the protein levels of sGCα1 and sGC in both P637H +/+ and P637H + mice were decreased both at baseline and after NO inhibitor treatment, and the cGMP levels were also significantly decreased. Consistenly, the activity of cGMP-dependent protein kinase1 (cGK-1) was supressed and the phosphorylation of its downstream substrate, myosin light chain, was increased in knock-in mice. Finally, the inhibitory effect on sGC proteins expression and NO/cGMP pathway activity were also observed in vitro on other 5 rare nonsynonymous variants of GUCY1A3 . In conclusion, our results demonstrate that GUCY1A3 defects contribute to hypertension by reducing the activity of NO/cGMP pathway, and support that rare varaints are important components of the genetic architecture of hypertension.