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Life is constituted of large group of macromolecule, functional and structural called “Protein,” made of amino acids (AA), and linked with peptide bonds with specific protein unique sequences. Variations in proteins are thought to have diverse effects with consequences on structure, stability, interactions, pH, enzymatic activity, abundance and other properties. Variants can be of genetic origin or it could occur de novo at the post-translational protein level. The sequence of amino acids defines protein structure and functions. Protein is involved in several critical functions like the physical cell-cell communication. Breakthrough in molecular science has shown that, to develop drugs for managing a disease-associated variations requires understanding of consequences of variants on the function of the affected protein and the impact on the pathways, in which protein is involved. Using biophysical/bioinformatics methods, immense amount of variation data generated is handled-connected to disease phenotypes. Obviously, there remain continuous needs for the combinations of genetic probing methods/bioinformatics, to predict single-nucleotide variations (SNV), for effective rational drug design that would embrace naturally occurring bioactive components of plant origin, towards the effective management of disease phenotype emanating from protein and amino acid variations. This, well thought out and synchronized concept, remains a way forward.