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Background Common variants in the gene GATA binding protein 4 ( GATA4) show association with alcohol dependence ( AD). The aim of this study was to identify rare variants in GATA4 in order to elucidate the role of this gene in AD susceptibility. Identification of rare variants may provide a more complete picture of the allelic architecture at this risk locus. Methods Sanger sequencing of all 6 coding exons of GATA4 was performed in 528 patients and 517 controls. Four in silico prediction tools were used to determine the effect of a DNA variant on the amino acid sequence and protein function. Five variants were included in the replication step. Of these, 4 were successfully genotyped in our replication cohort of 655 patients and 1,501 controls. All patients fulfilled DSM- IV criteria for AD, and all individuals were of German descent. Results In the discovery step, 19 different heterozygous variants were identified. Four patient-specific and potentially functionally relevant variants were followed up. Only the variant S379S (c.1137C>T) remained patient specific (1/1,166 patients vs. 0/1,997 controls). None of the variants showed a statistically significant association with AD. Conclusions The present study elucidated the role of GATA4 in AD susceptibility by identifying rare variants via Sanger sequencing and subsequent replication. Although novel patient-specific rare variants of GATA4 were identified, none received support in the independent replication step. However, given previous robust findings of association with common variants, GATA4 remains a promising candidate gene for AD. [ABSTRACT FROM AUTHOR]