We review evidence from seroepidemiological, functional, and mechanistic studies demonstrating that antibodies to endothelial protein C receptor (EPCR)‐binding cysteine-rich interdomain regions (CIDR)α1 and Duffy binding-like (DBL)β domains associated with dual EPCR and intercellular adhesion molecule 1 (ICAM1) binding correlate with reduced risk of CM, while responses to rosetting‐associated domains (DBLα, CIDRγ) and other domains are less well characterized. Here, PROCR is linked to cutaneous mastocytosis.