The Informational Spectrum Method (ISM) is the tool for the in silico analysis of proteins which interprets protein sequence linear information using signal analyses methods. In this paper the ISM was employed to characterize the products of genetic variants of tumor suppressor gene p53 and its natural binding regulator protein Mdm2. Based on this we propose the criterion for identification of missense mutations that have impact on the p53-Mdm2 feedback loop. The efficiency of the proposed criterion was confirmed by the ISM analyses of p53 mutants reported in: (i) healthy individuals, (ii) germline mutations database and (iii) somatic mutations database.