Transcription factors (TFs) regulate gene expression by binding to DNA sequences and modulating transcriptional activity through their effector domains. Despite the central role of effector domains in TF function, there is a current lack of a comprehensive resource and characterization of effector domains. Here, we provide a catalog of 924 effector domains across 594 human TFs. Using this catalog, we characterized the amino acid composition of effector domains, their conservation across species and across the human population, and their roles in human diseases. Furthermore, we provide a classification system for effector domains that constitutes a valuable resource and a blueprint for future experimental studies of TF effector domain function. Soto et al. present a catalog of 924 literature-curated human transcription factor effector domains. This catalog is used to describe the biophysical properties of effector domains, their evolutionary conservation, disruption in proteoforms, and relevance in human disease. Finally, a novel effector domain classification is provided.