The transforming growth factor-beta (TGFB) pathway has substantial impact on cellular functions, cell proliferation, and apoptosis. We used bioinformatics, gene expression, and cell biological assays to evaluate the functionality of frequent inherited germline polymorphisms in the TGFB receptor 1 (TGFBR1).In an exploratory (n=55) and confirmatory (n=106) study, we analyzed the TGFB1 pathway after incubation with TGFbeta1 ligand and after exposure to X-rays in peripheral blood human mononuclear cells. Expression of TGFB pathway genes was assessed by real-time PCR, and cellular viability was analyzed by flow cytometry. A total of six polymorphisms including the deletion variant (*6A) were identified to tag currently known common genetic variations in TGFBR1 and were analyzed in relation to the phenotypes.In accordance with a negative feedback mechanism, incubations with the ligand TGFbeta1 was followed by up-regulation of the intracellular SMAD7 and down-regulation of the SMAD3 mRNA molecules. The TGFBR1*6A deletion variant attenuated the suppression of SMAD3 in response to TGFbeta1 (P=0.02, in both studies). Moreover, cells harboring *6A were more sensitive toward cytotoxic effects of irradiation (P=0.001 after adjustment for age and sex). Cells were particularly prone toward radiation toxicity when carrying, in addition to *6A, the variant allele of rs11568785, which exhibits a strong genetic selection signature.The *6A deletion and the linked rs11568785 polymorphisms seem to attenuate TGFB signaling. This should be considered not only for clinical-epidemiological studies on cancer susceptibility but may also be relevant for side effects from drugs or radiotherapy.