In this study, we identified the most deleterious non-synonymous SNP of ERBB2 (HER2) receptors by its stability and investigated its binding affinity with herceptin. Out of 135 SNPs, 10 are nsSNPs in the coding region, in which one of the nsSNP (SNPid rs4252633) is commonly found to be damaged by I-Mutant 2.0, SIFT and PolyPhen servers. With this effort, we modelled the mutant HER2 protein based on this deleterious nsSNP (rs4252633). The modeled mutant showed less stability than native HER 2 protein, based on both total energy of the mutant and stabilizing residues in the mutant protein. This is due to a deviation between the mutant and the native HER2, having an RMSD of about 2.81 Å. Furthermore, we compared the binding efficiency of herceptin with native and mutant HER2 receptors. We found that herceptin has a high binding affinity with mutant HER2 receptor, with a binding energy of −24.40 kcal/mol, as compared to the native type, which has a binding energy of −15.26 kcal/mol due to six-hydrogen bonding and two salt bridges exist between herceptin and the mutant type, whereas the native type establishes four hydrogen bonds and two salt bridges with herceptin. This analysis portrays that mutant type has two additional hydrogen bonds with herceptin compared with the native type. Normal mode analysis also showed that the two amino acids, namely Asp596 and Glu598 of mutant HER2, forming additional hydrogen bonding with herceptin, had a slightly higher flexibility than the native type. Based on our investigations, we propose that SNPid rs4252633 could be the most deleterious nsSNP for HER2 receptor, and that herceptin could be the best drug for mutant compared to the native HER2 target. To cite this article: R. Rajasekaran et al., C. R. Biologies 331 (2008).