Protein complexes mediated by protein-protein interactions are essential for many cellular functions. TGF- signaling involves a cascade of protein-protein interactions and malfunctioning of this pathway has been implicated in human diseases. Using an in silico approach, we analyzed the naturally occurring human genetic variations from the proteins involved in the TGF- signaling (10 TGF- proteins and 242 other proteins interacting with them) to identify the ones that have potential biological consequences. All proteins were searched in the dbSNP database for the presence of non-synonymous single nucleotide polymorphisms (nsSNPs). A total of 118 validated nsSNPs from 63 proteins were retrieved and analyzed in terms of a) evolutionary conservation status, b) being located in a functional protein domain or motif, and c) altering putative protein motif or phosphorylation sites. Our results indicated the presence of 31 nsSNPs that occurred at evolutionarily conserved residues, 37 nsSNPs were located in protein domains, motifs, or repeats, and 46 nsSNPs were predicted to either create or abolish putative protein motifs or phosphorylation sites. This is a study undertaken to analyze the human genetic variations that can affect the protein function and the TGF- signaling. The nsSNPs reported in this manuscript can be characterized by experimental approaches to elucidate their exact biological roles and whether they are related to human disease.