The sphingosine-1-phosphate receptor (S1PR) family has been identified to be critical to a multitude of cellular functions including: cytoskeletal rearrangement, cellular motility and invasion, angiogenesis, immunological processes, and vascular maturation. In addition, the family is ubiquitously expressed throughout cell types. S1P receptors are also clinically relevant, being targeted in multiple sclerosis, cancers and recently COPD. Here we have used multiple model systems to explore how natural variants (SNPs) in human populations affect the sphingosine-1-phosphate (S1P) family of G protein-coupled receptor receptors. Variants rs61734752 (A11D) in the N-terminus of S1PR1 and rs3745268 (R60Q) and rs117064827 (V286A) in transmembrane domains 1 and 7, respectively, of S1PR2 significantly decreased the potency of the natural ligand, S1P. Variant rs35483143 (L318Q), in the C-terminus of S1PR5, disrupts the ability of the receptor to couple to Gα12, one of the two cognate Gα proteins through which the receptor elicits downstream responses. RNA sequencing analysis of transfected HEK293T cells showed decreases in transcripts pertaining to cytoskeletal rearrangement, cell motility, and RhoGEF effector signaling when comparing the variant and wild type receptors. Analysis of F-actin dynamics reveal a substantial decrease in overall F-actin in variant receptor transfected cells. Further analysis of variants is being undertaken to investigate the signaling defects to cellular and developmental homeostasis.