Background: Cerebral cavernous malformations (CCMs) are vascular disorders with a diverse natural history causing stroke and epilepsy. This multicenter cohort study aimed to unravel the correlation between genotype and clinical presentation in CCMs. Methods: We conducted a multicenter cohort study across three reference centers in China. In this study, we employed whole-exome sequencing, droplet digital PCR, and targeted panel sequencing to analyze 290 surgical specimens of CCMs. We also conducted an observational study of patients managed conservatively prior to surgical resection of CCMs to elucidate their natural history. Findings: Between January 2013 and May 2023, 201 out of 290 surgically resected CCMs had mutations in MAP3K3, PIK3CA, or CCM germline mutations, and were subsequently included in further analysis. Patients with solitary PIK3CA mutations exhibited a higher likelihood of hemorrhage (P < .001), while those with MAP3K3 mutations were more prone to epilepsy onset (P < .001). The mutation spectrum correlated with various clinical parameters, influencing hemorrhage risk (P < .001), lesion diameter (P = .020), onset of non-hemorrhage epilepsy (P < .001), Zabramski classifications (P < .001), DVA (P < .001) and edema in the MRI appearance (P < .001). Over the study period, patients with PIK3CA mutations showed significantly higher 1-, 2-, and 5-year cumulative risks of hemorrhage (34.8%, 51.7%, and 62.7%, respectively) higher cumulative risks of hemorrhage compared to MAP3K3 mutations (P < .017) and double mutations (P < .001). Adjusted analyses confirmed the increased risk of subsequent hemorrhage in patients with PIK3CA mutations (adjusted HR = 8.816, 95% CI: 1.478-9.855, P = .045). Independent risk factors for epilepsy included age of onset (adjusted OR = 0.956, 95% CI: 0.928-0.983, P = .002), lesion diameter (adjusted OR= 0.545, 95% CI: 0.325-0.914, P = .021), and lesion locations (adjusted OR = 0.545, 95% CI: 0.325-0.914, P < .001). Notably, patients with germline mutations experienced earlier symptom onset (P = .003) and larger lesions (P = .019) compared to those with somatic mutations. Interpretation: This study's findings highlight a significant correlation between CCM genotype and clinical phenotypes, particularly regarding hemorrhage risk and seizures. The results offer insights into predicting the clinical course of CCM patients with different phenotypes, potentially leading to personalized treatment adjustments.Funding: National Natural Science Foundation of China (No. 82220108010, 81971104, 82201440, 82122020, 82101369, 82102009 and 82330038). Beijing Municipal Commission of Education (BPHR20220113).Declaration of Interest: Tao Hong, Hongqi Zhang, Jian Ren report grants from National Natural Science Foundation of China. Tao Hong reports grants from Beijing Municipal Commission of Education. Hongqi Zhang, and Tao Hong declare no competing interests.Ethical Approval: This study was conducted in compliance with the approval of the local ethics committee and involved a prospectively maintained database. Furthermore, all patients provided informed consent, or consent was obtained from their legal guardian in cases involving participants with cognitive impairment or those aged younger than 18 years.