Sphingosine‐1 phosphate receptor‐1 (S1P1) activation maintains endothelial barrier integrity, whereas S1P1 desensitization induces peripheral blood lymphopenia. The latter is exploited in the approval and/or late‐stage development of receptor‐desensitizing agents targeting the S1P1 receptor in multiple sclerosis, such as siponimod, ozanimod, and ponesimod. SAR247799 is a recently described G protein‐biased S1P1 agonist that activates S1P1 without desensitization and thus has endothelial‐protective properties in patients without reducing lymphocytes. As SAR247799 demonstrated endothelial‐protective effects at sub‐lymphocyte‐reducing doses, the possibility exists that other S1P1 modulators could also exhibit endothelial‐protective properties at lower doses. To explore this possibility, we sought to quantitatively compare the biased properties of SAR247799 with the most advanced clinical molecules targeting S1P1. In this study, we define the β‐arrestin pathway component of the impedance profile following S1P1 activation in a human umbilical vein endothelial cell line (HUVEC) and report quantitative indices of the S1P1 activation‐to‐desensitization ratio of various clinical molecules. In a label‐free impedance assay assessing endothelial barrier integrity and disruption, the mean estimates (95% confidence interval) of the activation‐to‐desensitization ratios of SAR247799, ponesimod, ozanimod, and siponimod were 114 (91.1–143), 7.66 (3.41–17.2), 6.35 (3.21–12.5), and 0.170 (0.0523–0.555), respectively. Thus, we show that SAR247799 is the most G protein‐biased S1P1 agonist currently characterized. This rank order of bias among the most clinically advanced S1P1 modulators provides a new perspective on the relative potential of these clinical molecules for improving endothelial function in patients in relation to their lymphocyte‐reducing (desensitization) properties.