The homohexameric AAA+ ATPase p97 plays an important role in protein homeostasis in the cell. Missense mutations in the p97 gene cause 50% of multisystem proteinopathy (MSP) and it can affect the muscles, bone, and brain. Most of the mutations are clustered at the N-D1 interface and one such most clinically relevant mutation is R155P. This variant has been found to form hexamer in the same way as its wild type counterpart and has an increased ATPase activity. However, the effect of this mutation on the structure-function behavior of p97 is not deciphered yet. Herein, with the aid of the state-of-the-art high-resolution single-particle cryo-EM technique, the structure of p97R155P with nucleotide was solved at near-atomic resolutions. According to the results, the mutant changes the conformation of the p97 during the ATPase cycle which would affect the interaction with substrate and cofactors. Analysis of the structural information will enable us to address the effect of the disease-causing mutation and uncovers the molecular basis of nucleotide-dependent conformational changes, driving p97 function, and design drugs that target the p97 specifically.