In this work, the most detrimental missense mutations of p110α that cause various types of cancer were identified computationally and the binding efficiencies of those missense mutations with regulatory subunit p85 were analyzed. Out of 30 missense mutations, I-Mutant 2.0, SIFT and PolyPhen programs identified 11 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 11 variants was performed to understand the change in their conformations with respect to the native p110α by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 11 mutants were docked with the regulatory subunit p85 to explain the binding efficiencies of those detrimental missense mutations. Among the 11 mutants, 10 mutants were identified as deleterious based on the results of docking studies, RMSD scores and intra-molecular interactions. Finally, normal mode analysis determined that the loss of binding affinity of these 10 mutants was caused by altered flexibility in the amino acids that bind to p85 compared with the native protein. Thus, the present study showed that all the regulatory subunit binding amino acids in those 10 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant p110α and p85. Copyright © 2013 American Scientific Publishers.