Abstract Mutations in adenosine triphosphate (ATP)-binding cassette transporter 1 (ABCA1) gene have been established as the molecular defect in Tangier disease and familial hypoalphalipoproteinemia, uncommon genetic disorders characterized by deficient or depressed high-density lipoprotein (HDL) cholesterol and increased triglycerides. However, information regarding the frequency of common variants, including Arg219Lys (R219K) within the coding region of the ABCA1 gene and their effect on these phenotypes in the general population is limited. This study examined the frequency and phenotypic effect of R219K variant in a community-based sample of 887 white and 390 black young adults aged 20 to 38 years. The frequency of the variant allele (K219) was higher in blacks than in whites (0.595 v 0.262, P < .001), with carriers (KK+RK) representing 83.8% of blacks versus 44.2% of whites. After adjusting for age, body mass index (BMI), and sex, the genotype effect on HDL cholesterol and natural logarithm of triglycerides was not apparent in whites or blacks. However, significant interaction effects of genotype and age on HDL cholesterol ( P < .001) and genotype and BMI on triglycerides ( P = .029) were found in whites. Carriers (KK+RK), unlike noncarriers (RR) showed a positive relationship between age and HDL cholesterol (regression coefficient β = 0.28, P = .029 for carriers v β = −0.18, P = .112 for noncarriers). In addition, the variant allele attenuated the adverse positive relationship between BMI and triglycerides (β = 0.032, P < .001 for carriers v β = 0.046, P < .001 for noncarriers). These results indicate that the K219 allele frequency differs markedly between blacks and whites, and that the variant-allele modulates the association between age and HDL cholesterol, as well as body fatness and triglycerides in a beneficial manner only in whites.