Abstract System level analysis of the cellular signaling processes helps to understand the perturbations due to gene expression or through protein-protein interactions. In the case of colorectal cancer (CRC), a large proportion of patients display mutational inactivation of multiple pathways. Specifically, TGFβ-signaling is postulated to be one of the major contributors among them. The vast variety of studies to date considered the role of TGFβR1 and TGFβR2 receptors in CRC progression and relatively fewer studies targeted the Transforming growth factor-β1 (TGFβ1) protein. Therefore, this remains a poorly understood mechanism. TGFβ1 is the most abundant and universally expressed isoform, which is secreted into the extracellular matrix as a latent protein and is the important regulator of the cellular proliferation. Increased expression of TGFβ1 allows immunogenic cell lines to escape immunosurveillance and thus form tumors. Till date, no study has focused on the complete aspect of the TGFβ1 effects. Here, we investigated the consequences of 37 ns-SNPs in the TGFβ1 gene through computational tools and four ns-SNPs L28F (rs199946261), G46R (rs768250306), N69Y (rs763943753), and L83R (rs541829714) were identified that are highly likely to affect the structure, function, and activity of the TGFβ1 protein. Network motifs were also identified for the concerned pathway in the quest for functional annotation. In our study, we have performed a combination of network and structure-based analysis to elucidate the role of candidate genes for the TGFβ signaling pathway and to infer the mutational effect on the TGFβ1 gene and their relationship towards CRC progression.