The serine incorporator (SERINC) family of proteins are a family of multipass transmembrane proteins associated with biosynthesis of serine-containing phospholipids and sphingolipids. Humans have 5 paralogs, SERINC1-5, which have been linked to disease including variable expression in tumor lines and possessing activity as restriction factors against HIV-1. Despite recent studies, the cellular function of SERINC proteins have yet to be fully elucidated. The goal of this study as to investigate the role of SERINC3 by expanding upon its interactome. We used a variety of bioinformatic tools to identify cellular factors that interact with SERINC3 and assessed how sequence variation might alter these interactions. Analysis of the promoter region indicates that SERINC3 is putatively regulated by transcription factors involved in tissue-specific development. Analysis of the unique 3′-untranslated region of one variant of HsSERINC3 revealed that this region serves as a conserved site of regulation by both RNA binding proteins and miRNA. In addition, SERINC3 is putatively regulated at the protein level by several posttranslational modifications. Our results show that extra-membrane portions of SERINC3 are subject to variation in the coding sequence as well as areas of relatively low conservation. Overall, our data suggest that regions of low homology as well as presence of variations in the nucleotide and protein sequences of HsSERINC3 suggest that these variations may lead to aberrant function and alternative regulatory mechanisms in homologs. The functional consequences of these sequence and structural variations need to be explored systematically to fully appreciate the role of SERINC3 in both health and disease.