MAPK3 and cerebral cavernous malformation: On the other hand, recent whole-exome sequencing (WES) studies have shown that sporadic CCMs are mainly caused by somatic mutations in either phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) or mitogen-activated protein kinase kinase kinase 3 (MAP3K3) genes, whereas somatic mutations in three known CCM genes are comparatively very rare, thus defining a new subclass of CCM (CCM4, MIM#619538) [14,15,16].