This study evaluated the underlying mechanistic links between genetic variability in vitamin K metabolic pathway genes ( and ) and phylloquinone hydroxylation activity using genotype- and haplotype-based approaches. Specifically, we characterized genetic variability in the locus and compared common single allele genotypes and common haplotypes as predictors of hepatic gene expression, enzyme abundance, and phylloquinone (VK) ω-hydroxylation kinetics. We measured and mRNA levels, CYP4F2 and CYP4F11 protein abundances, and the VK concentration-dependent ω-hydroxylation rate in matched human liver nucleic acid and microsome samples, utilizing a novel population modeling approach. Results indicate that accounting for the allele alone is sufficient to capture most of the genetic-derived variability in the observed phenotypes. Additionally, our findings highlight the important contribution that CYP4F11 makes toward vitamin K metabolism in the human liver.