TP53 alteration is the most frequent genetic alteration found in human cancers. To date, more than 15,000 tumors with TP53 mutations have been published, leading to the description of more than 1,500 different TP53 mutants (http://p53.curie.fr). The frequency of these mutants is highly heterogeneous, with 11 hotspot mutants found more than 100 times, whereas 306 mutants have been reported only once. So far, little is known concerning the biological significance of these rare mutants, as the majority of biological studies have focused on classic hotspot mutants. In order to gain a deeper knowledge about the significance of all of these mutants, we have cross-checked each mutant of the TP53 mutation database for its activity, derived from a library of 2,314 TP53 mutants representing all possible amino acid substitutions caused by a point mutation. The transactivation activity of all of these mutant was analyzed with respect to eight transcription promoters [Kato S, et al., Proc Natl Acad Sci USA (2003)100:8424-8429]. Although the most frequent TP53 mutants sustain a clear loss of transactivation activity, more than 50% of the rare TP53 mutants display significant activity. Analysis in specific types of cancer or in normal skin patches demonstrates a similar distribution of TP53 loss of activity, with the exception of melanoma, in which the majority of TP53 mutants display significant activity. Our data indicate that TP53 mutants represent a highly heterogeneous population with a large diversity in terms of loss of transactivation activity that could account for the heterogeneous tumor phenotypes and the difficulty of clinical studies.