XPD acts as a functional helicase and aids in unwindingdouble helix around damaged DNA, leading to efficient DNA repair. Mutations of XPD give rise to DNA-repair deficiency diseasesand cancer proneness. In this study,cancer-causing missense mutation that could inactivate helicase function and hinderits binding with other complexes were analysed usingbioinformatics approach. Rigorous computational methodswere employed to understand the molecular pathogenic profile of mutation. The mutant model with the desired mutation was built with I-TASSER. GROMACS 5.0.1 was used to evaluate the effect of a mutation on protein stability and function. Of the 276 missense mutations, 64 were found to be disease-causing. Out of these 64, seven were of cancer-causing mutations. Among these, we evaluated K48R mutationin a computational simulated environment to determine its impact on protein stability and function since K48position was ascertained to be highly conserved and substitutionwith arginine could impair the XPD activity. Molecular Dynamic Simulation and Essential Dynamics analysis showed thatK48R mutation altered protein structural stabilityand produced conformational drift. Our predictions thus revealed that K48R mutation could impairthe XPDhelicase activity and affectits ability to repair the damaged DNA, thus augmenting the risk for cancer.