SignificanceXeroderma pigmentosum (XP) is a genodermatosis that occasionally causes neurological abnormalities because of impaired DNA repair. The XPF endonuclease, compromised in the XP-F complementation group patients, is vital for genome maintenance. Patients completely lacking the XPF functionality are extremely rare and die in early infancy from fatal malformations. Other XP-F cases are still rare (<1% worldwide-XP), but they exhibit milder manifestations with residual XPF actibities. From the largest Japanese XP-cohort study, we identified 17 cases with previously uncharacterizedERCC4/XPFdeep intronic founder mutations. One mutation accounts for approximately 10% of all Japanese XP patients (MAF = 0.002). Most cases developed early-onset skin cancers, necessitating critical attention to these mutations. Artificial antisense-oligonucleotide–based therapeutics hold promise for high-frequency XP cases with intron mutations.