Abstract: TP53 plays critical roles in maintaining genome stability. Deleterious genetic variants damage the function of TP53, causing genome instability and increased cancer risk. Of the large quantity of genetic variants in TP53 identified, however, many remain functionally unclassified as variants of unknown significance (VUS) due to a lack of evidence. This is reflected by the pres-ence of 749 (42%) variants as VUS in the 1,785 germline variants collected in the ClinVar data-base. In this study, we addressed the issue of deleteriousness of TP53 missense VUS. Through uti-lizing protein structure-based Ramachandran Plot-Molecular Dynamics Simulation (RPMDS) method, we measured the effects of missense VUS variants on TP53 structural stability. Of the 353 missense VUS tested, we observed deleterious evidence for 204 VUS, as reflected by the TP53 structural changes caused by the VUS-substituted residues. We compared the results from RPMDS with these by other in silico methods and observed higher specificity of RPMDS in classi-fication of TP53 missense VUS than these methods. Data from our current study ease a long standing challenge in classifying the missense VUS variants in TP53, one of the most important tumor suppressor genes.