AbstractFollowing recent genome wide association studies (GWAS), significant genetic associations have been identified for several genes with nonsyndromic cleft lip with or without cleft palate (CL(P)). To replicate two of these GWAS signals, we investigated the role of common and rare variants in thePAX7andVAX1genes. TaqMan genotyping was carried out for SNPs inVAX1andPAX7and transmission disequilibrium test (TDT) was performed to test for linkage and association in each population. Direct sequencing in and around thePAX7andVAX1genes in 1,326 individuals of European and Asian ancestry was done. The TDT analysis showed strong associations with markers inVAX1(rs7078160,P = 2.7E−06 and rs475202,P = 0.0002) in a combined sample of Mongolian and Japanese CL(P) case–parent triads. Analyses using parent‐of‐origin effects showed significant excess transmission of the minor allele from both parents with the effect in the mothers (P = 6.5E−05, OR (transmission) = 1.91) more striking than in the fathers (P = 0.004, OR (transmission) = 1.67) forVAX1marker rs7078160 in the combined Mongolian and Japanese samples when all cleft types were combined. The rs6659735 trinucleotide marker inPAX7was significantly associated with all the US cleft groups combined (P = 0.007 in all clefts andP = 0.02 in CL(P)). Eight rare missense mutations found inPAX7and two rare missense mutations inVAX1. Our study replicated previous GWAS findings for markers inVAX1in the Asian population, and identified rare variants inPAX7andVAX1that may contribute to the etiology of CL(P). Determining the role of rare variants clearly warrants further investigation. © 2013 Wiley Periodicals, Inc.