The human aromatase protein encoded by CYP19A1 gene is the principle enzyme involved in the biogenesis of oestrogen in adipose tissues. An excessive exposure to endogenous oestrogen is regarded as an important determinant in the risk of breast cancer. Thus, in the present study we have used multiple computational methods to identify the most deleterious nonsynonymous SNPs in CYP19A1 gene that caused probable genotypic–phenotypic alterations susceptible to breast cancer malignancy. In this study, a total of 338 nsSNPs werescreened using 12 in silico tools including SIFT, PROVEAN, PolyPhene-2, SNAP2, I Mutant 3.0, MuPro, mCSM, PhD SNP, SNP&GO, P-Mut, Dr Cancer, and, CScape. Additionally the structural and functional consequences of missense mutations were validated using Consurf, ModPred, SOPMA, and, HOPE server tools. Of the 338 nsSNPs subjected to functional, protein stability, disease associated, and, cancer susceptible analysis, 14 variants were predicted to be highly deleterious mutants. Further, structural and molecular studies suggested10 variants (R435H, Y77C, Y81C, E302K, E210K; and L451P, G49D, G131D, L204W and D309) to have various deformities and caused structural disturbances of the protein. Through the combination of multiple computational tools and strategized analysis, we report seven novel high risk nsSNPs of human aromatase enzyme in association with the pathogenesis of human breast cancer