Hereditary Hemorrhagic Telangiectasia (HHT) and Juvenile Polyposis Syndrome (JPS) can be caused by deleterious variants in the SMAD4 gene, which is part of the TGFß/BMP signaling pathway. We developed a functional assay for SMAD4 variants that allows discrimination between benign and pathogenic SMAD4 variants. We found that all the variants tested led to a loss of function in the SMAD4 protein. Most of these variants impaired SMAD4 association with other SMAD proteins. This assay will be transferable to clinical genetic laboratories and will improve the diagnosis of HHT-JPS patients. (By Dr. Agnès Desroches-Castan, https://jmg.bmj.com/content/early/2025/08/19/jmg-2025-110797 )