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Cutaneous melanoma is the most aggressive of skin tumors. In order to discover new biomarkers that could help us improve prognostic prediction in melanoma patients, we have searched for germline DNA variants associated with melanoma progression. Thus, after exome sequencing of a set of melanoma patients and healthy control individuals, we identified rs1042602, an SNP within TYR, as a good candidate. After genotyping rs1042602 in 1025 patients and 773 healthy donors, we found that the rs1042602-A allele was significantly associated with susceptibility to melanoma (CATT test: p = 0.0035). Interestingly, we also observed significant differences between patients with good and bad prognosis (5 years of follow-up) (n = 664) (CATT test for all samples p = 0.0384 and for men alone p = 0.0054). Disease-free-survival (DFS) analyses also showed that patients with the A allele had shorter DFS periods. In men, the association remained significant even in a multivariate Cox Proportional-hazards model, which was adjusted for age at diagnosis, Breslow thickness, ulceration and melanoma subtype (HR 0.4; 95% confidence interval (CI) 0.20–0.83; p = 0.0139). Based on our results, we propose that rs1042602-A is a risk allele for melanoma, which also seems to be responsible for a poorer prognosis of the disease, particularly in men. This research was funded by grants from the Department of Economic Development, Sustainability and the Environment of the Basque Government (Spain) (KK2017-041 and KK2020-00069 to M.D.B. and S.A.), the Basque Government (Basque Country Research Groups IT1693-22 to S.A. as Co IP), the University of the Basque Country (UPV/EHU) (GIU17/066 to M.D.B.), the Spanish Ministry of Science and Education (MINECO) (PCIN-2015-241 to M.D.B.) and by the ECSEL JU European project ASTONISH (grant number 692470 to M.D.B.).