Jägle S, Heeg M, Grün S, et al. - Given germline STAT3 gain-of-function (GOF) mutations have been associated with poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance, researchers focused on the influence of 17 diverse STAT3 GOF mutations on the canonical STAT3 signaling pathway. They also correlated the molecular outcomes with clinical manifestations. Three groups of mutations were defined. In Group 1, changed STAT3 phosphorylation kinetics and strong basal transcriptional activity was demonstrated by mutants. Link with the highest penetrance of lymphoproliferation and autoimmunity was shown by these. A strongly inducible transcriptional reporter activity was exhibited by Group 2 mutants and they were clinically less penetrant. In Group 3, the mutants were mostly placed in the DNA binding domain and displayed the strongest DNA binding affinity, however, a poor transcriptional reporter response was shown by these. Therefore, a heterogeneous response pattern at the molecular level determined the GOF influence of STAT3 mutations. A significant contribution of mutation-determined influences on disease manifestations was suggested by the observed correlation of response pattern and clinical penetrance.