Phospholipids are asymmetrically distributed in the plasma membrane (PM), and scramblases disrupt this asymmetry by shuffling phospholipids. We recently identified mouse Tmem63b as a membrane structure‐responsive scramblase. Tmem63b belongs to the TMEM63/OSCA family of ion channels; however, the conservation of the scramblase activity within this family remains unclear. We expressed human TMEM63 paralogs, TMEM63B orthologs, and plant OSCA1.1 in Tmem63b‐deficient mouse pro‐B cells and found that vertebrate TMEM63B orthologs exhibit scramblase activity at the PM. Previously, ten pathogenic human TMEM63B variants were identified, some of which exhibited constitutive scramblase activity. Upon expressing all variants, we found that nine variants displayed constitutive scramblase activity. These results suggest that membrane structure‐responsive scramblase activity at the PM is conserved among vertebrate TMEM63B orthologs.