ERBB2 (HER2) is a well-studied oncogene with several driver mutations apart from the well-known amplification defect in some breast cancers. We used the GigaAssay to test the functional effect of HER2 missense mutations on its receptor tyrosine kinase function. The GigaAssay is a modular high-throughput one-pot assay system for simultaneously measuring molecular function of thousands of genetic variants at very high accuracy. The activities of 5,886 mutations were classified, significantly more than mutants previously reported. These variants include 112 new in vitro, 10 known, and 9 new in vivo gain-of-function (GOF) mutations. Many of the GOFs spatially cluster in sequence and structure, supporting the activation mechanisms of heterodimerization with EGFR and release of kinase inhibition by the juxtamembrane domain. Retrospective analysis of patient outcomes from the Genomic Data Commons predicts increased survival with the newly identified HER2 GOF variants.