Pathogenic monoallelic variants in TGFBR1/2 as well as in SMAD3 predispose to IBD, strengthening the key role of the SMAD3 canonical pathway for maintaining intestinal homeostasis, a role previously supported by GWAS studies in common multifactorial forms of IBD (1) as well as by Smad3 inactivation in mice (53, 54). Here, SMAD3 is linked to inflammatory bowel disease.