Purpose: Common polymorphic variants upstream of Zinc finger protein gene 469 (ZNF469) have been associated with central corneal thickness. Rare ZNF469 variants have been shown in keratoconus patients. The aim of the current study was to investigate the frequency of ZNF 469 gene variants in rapidly progressive advance keratoconus patients who underwent corneal transplant surgery by the age of 30, compared to their frequency in the normal Turkish population.Methods: A search in a patient database was performed to identify patients with a rapidly progressive keratoconus requiring corneal transplant surgery by the age of 30 in at least one eye. Twenty-six advance keratoconus patients (study group) and 109 health subjects (control group) were included in the study. Blood samples were donated, and genomic DNA was extracted. The entire coding sequence of the ZNF469 gene including the 84 bp of the putative intron was amplified using PCR primers and analyzed using next generation sequencing (NGS).Results: Fifteen single nucleotide polymorphisms previously reported and registered to the dbSNP database were detected in the study group. The allele frequencies of these polymorphisms were higher in the keratoconus group compared to the control group and to the ExAC genome database. Three new missense heterozygote variants and one new synonym variant were detected in keratoconus group. According to prediction software, the P873T and Q2188H variants were shown to be non-tolerated, whereas G3424S could be tolerated. The synonymous variant R1060R is not predicted to lead to abnormal splicing by Human Splicing Finder in silico analysis.Conclusion: New detected ZNF 469 P873T and Q2188H heterozygote coding variants in isolated advance keratoconus patients may be associated with the disease pathogenesis.