AimsConjunctival melanoma (CoM) is a rare but highly lethal ocular melanoma and there is limited understanding of its genetic background. To update the genetic landscape of CoM, whole-exome sequencing (WES) and targeted next-generation sequencing (NGS) were performed.MethodsAmong 30 patients who were diagnosed and treated at Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, from January 2018 to January 2023, WES was performed on 16 patients, while targeted NGS was conducted on 14 patients. Samples were analysed to identify the mutated genes, and the potential predictive factors for progression-free survival were evaluated. Furthermore, the expression of the mutated gene was detected and validated in a 30-patient cohort by immunofluorescence.ResultsMutations were verified in classic genes, such asBRAF(n=9),NRAS(n=5) andNF1(n=6). MutatedFAT4andBRAFwere associated with an increased risk for the progression of CoM. Moreover, decreased expression of FAT4 was detected in CoM patients with a worse prognosis.ConclusionsThe molecular landscape of CoM in Chinese patients was updated with new findings. A relatively high frequency of mutatedFAT4was determined in Chinese CoM patients, and decreased expression of FAT4 was found in patients with worse prognoses. In addition, bothBRAFmutations andFAT4mutations could serve as predictive factors for CoM patients.