F508

F508 refers to a common mutation in the CFTR gene, most often written as F508del. It corresponds to a deletion of three nucleotides (c.1521_1523delCTT) that removes amino acid phenylalanine at position 508. This mutation is the most frequent cause of cystic fibrosis worldwide.

In inheritance terms, F508del is an autosomal recessive CF-causing variant. It accounts for a large majority of CFTR mutations in people of European ancestry; the F508del allele is present in about 60–70% of CF alleles in many European populations, and the carrier frequency in the general population is roughly 1 in 25.

Molecularly, F508del is classified as a class II CFTR mutation. The CFTR protein with this mutation misfolds in the endoplasmic reticulum and is largely degraded before reaching the cell surface, resulting in markedly reduced chloride and bicarbonate transport across epithelial cells. This leads to thick, sticky mucus and dysfunction in multiple organs, most notably the lungs and pancreas.

Treatment increasingly targets F508del with CFTR modulator therapies. Correctors such as lumacaftor, tezacaftor, and elexacaftor improve the trafficking and folding of CFTR; potentiators like ivacaftor enhance channel activity. A triple combination of elexacaftor, tezacaftor, and ivacaftor has shown substantial clinical benefit for patients with at least one F508del allele. Nomenclature wise, F508del is also referred to as p.Phe508del in HGVS notation.