Supravalvular aortic stenosis (SVAS) as an inherited vascular disease is caused by mutation in the elastin gene (ELN). The present study reports on two Japanese siblings with an identical genetic mutation, but different clinical course of SVAS. A 12 year old sister developed a severe hour-glass SVAS with a peak gradient of 91 mmHg, associated with a mild pulmonary arterial stenosis, while the 10 year old younger sister has mild SVAS (peak gradient 12 mmHg), but was found to have a moderate valvular and supravalvular pulmonary stenosis. The elder sister, with severe stenosis, underwent surgical replacement of the ascending aorta when she was 4 years old. Molecular analysis was able to detect a novel nonsense mutation in exon 21 of the (ELN) gene, consisting of a transition of C to G at position 1371, determining a stop codon at position 457 (Y457X) in both children. The mutated gene encodes a truncated protein missing a large portion of the C-terminal domains including essential assembly domains. These data indicate the variable phenotype of SVAS associated with Y457X mutations. Further study on genetic and environment factors that alter the SVAS development is needed for understanding of the etiology of this entity.