SMAD6 is an inhibitory SMAD protein that negatively regulates multiple signaling pathways, particularly the TGF-β and BMP pathways. As an intracellular mediator, SMAD6 blocks BMP-SMAD1 signaling by competing with SMAD4 for receptor-activated SMAD1 binding, thereby inhibiting downstream transcriptional responses 1. The protein functions as a critical regulator in tissue development and homeostasis, with SMAD6 upregulation serving to block TGF-β signaling pathways in hepatic stellate cells 2. SMAD6 also plays important roles in pulmonary fibrosis regulation and myofibroblast differentiation processes 34. Disease-wise, SMAD6 variants are significantly associated with craniosynostosis, particularly metopic synostosis, with an 18.3-fold enrichment of loss-of-function variants compared to population controls 5. The gene is also linked to congenital heart diseases including bicuspid aortic valve and aortic aneurysms 6, as well as primary open-angle glaucoma 1. Additionally, SMAD6 variants have been identified in autism spectrum disorder and intellectual disability cases 7. The remarkable phenotypic diversity associated with similar SMAD6 variants suggests complex modifier mechanisms that remain poorly understood 8.