Objectives To identify the novel pathogenic genetic variants associated with intrahepatic cholestasis of pregnancy (ICP) disease by whole-exome sequencing (WES) approach. Design WES the DNA, and conduct association between genetic variants and total bile acids. Setting Jiangxi. Samples 151 ICP patients. Methods DNA samples from 151 ICP patients were subjected to WES. Rare novel exonic variants (minor allele frequencies: MAF < 1%) were performed for subsequent analysis. Main outcome measures Association of genetic variants with ICP and other clinical disorders. Results We detected 42 were novel. We classified these loci as four panels according to the prediction results, of which, 7 novel possible pathogenic mutations were identified which located in the known functional genes including ABCB4, ABCB11 and ABCC2 for first reported in damaging group. Besides, compare to reference, ABCC2 Ser1342Tyr modified protein structure showed a slight change in the chemical bond lengths of ATP-ligand binding amino acid side chains. And in placental tissue, the expression level of ABCC2 gene in ICP patients was significantly higher than healthy pregnant women. Moreover, the patients with two mutations in ABC family genes have higher average value of TBA, AST, DBIL, CHOL, TG and HDL compared to the patients which have one mutation, no mutation in ICP and local controls. Conclusion Our results provide new insights into the genetic architecture of ICP disease. They may contribute to genetic diagnose of ICP disease, and provide new treatment for ICP patients. Keywords WES, TBA, ABC transporters’ genes, novel variants, ICP, ABCC2 gene, Ser1342Tyr mutation