Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome‐wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The “missing” heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low‐frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low‐frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low‐frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low‐frequency variants contribute to the genetic etiology of NSCL/P.