Cerebral cavernous malformations (CCMs) are a neurovascular anomaly that may occur sporadically or be inherited due to autosomal dominant mutations in KRIT1, CCM2 or PDCD10 (refs. ^{, , –}). Individual lesions are caused by somatic mutations that have been identified in KRIT1, CCM2, PDCD10, MAP3K3 and PIK3CA^{, , , , , –}. However, the interactions between mutations and their relative contributions to sporadic versus familial cases are unclear. We show that mutations in KRIT1, CCM2, PDCD10 and MAP3K3 are mutually exclusive but may co-occur with mutations in PIK3CA. We also find that MAP3K3 mutations may cause sporadic but not familial CCM. Furthermore, we find identical PIK3CA mutations in CCMs and adjacent developmental venous anomalies (DVAs), a common vascular malformation frequently found in the vicinity of sporadic CCMs^{, –}. However, somatic mutations in MAP3K3 are found only in the CCM. This suggests that sporadic CCMs are derived from cells of the DVA that have acquired an additional mutation in MAP3K3.