Cobalamin is an essential micronutrient in mammals. Deficiencies of this micronutrient have been implicated as risk factors for various complex diseases. Cobalamin is transported to the cells by the transport protein transcobalamin II (TCII), and hence genetic variations (like single nucleotide polymorphisms) in TCII could be perceived to affect the binding of cobalamin to TCII, thereby modulating the intracellular concentrations of cobalamin. To understand whether three nonsynonymous mutations in TCII (I5V, P241R, and R381Q) alter the structure of the protein which could potentially affect cobalamin binding, we performed molecular dynamics simulation in silico. Superimposition of active sites of the four simulated models (wild type and three variants) with the human TCII crystal structure revealed that the distance between the N epsilon nitrogen atom of His-173 and the cobalt ion of cobalamin deviated considerably in the I5V model as compared to wild type and other variants. His-173 directly coordinates with the cobalt ion of cobalamin. Further, from our dynamic cross-correlation and principal component analysis it appears that in the I5V model the beta-domain moves apart from the alpha-domain creating a wide gap between the two domains. This might facilitate the initial binding of cobalamin in the I5V model as cobalamin enters the binding site through the gap between the two domains. These observations were not found in the other variants. We thus speculate that binding of cobalamin will be more facile in the I5V variant.