Functional analysis of the two pathogenic missense variants originally reported to cause LRFH demonstrated normal EPHB4 protein expression levels but reduced protein activity.2 The analysis of 4 of the 20 missense variants reported to cause CM-AVM2 by Amyere et al. showed largely reduced protein expression levels with EPHB4 protein aggregated in intracellular inclusions.6 These findings led us to carry out a functional classification of the seven new variants for FH1-FH5, VA1–2, and PL1. Here, EPHB4 is linked to cutaneous mastocytosis.