Aim Based on DNA sequencing the Human Leukocyte Antigen (HLA) gene system is the most polymorphic one amongst the human genome. For many genes it is known that isoforms can be present due to alternative splicing. In the IPD-IMGT/HLA database, a number of structural splice variants for HLA have been described and annotated, based on DNA polymorphism in the splice site consensus sequence. But data on mRNA transcript sequences are still lacking. The lack of RNA/cDNA SBT analysis thus underestimates the actual number of HLA splice variants. In the present study, we performed cDNA sequencing to study alternative splicing of HLA-C. Methods RNA was isolated from fresh peripheral blood mononuclear cells of healthy individuals and from B cell lines using the Qiagen RNeasy kit, followed by cDNA synthesis with the Superscript III first-strand synthesis system from Thermo Fisher Scientific. Sanger Sequencing was performed after HLA-C group-specific amplification of cDNA. Twelve of the fourteen different HLA-C allele groups were studied, C * 17 and C * 18 were not available. Results Sequencing of HLA-C revealed the presence of different mRNA splice variants. One of the most intriguing splice variants involved exon 5 skipping. This mRNA variant is co-expressed together with the mature spliced transcript. The presence of this variant is depending on the allele group, implicating a role for polymorphism in this alternative splicing process. Furthermore, since exon 5 encodes the transmembrane region, the translation of this mRNA variant might result in soluble HLA-C molecules. Conclusions Some HLA-C allele groups show alternative splicing resulting in exon 5 skipping. The functional implication of this exon 5 skipping on the HLA-C expression and the influence on T and NK cell recognition is further investigated. [ABSTRACT FROM AUTHOR]