Mutations in the hepatocyte nuclear factor 1-beta gene (HNF1B; OMIM 604284) on chromosome 17cen-q21.3 cause MODY5. This protein is also known as transcription factor 2 (TCF2). HNF1B is highly homologous to HNF1A (MODY3), and these genes likely interact to regulate gene expression. Individuals with MODY5 mutations have a lower renal threshold to glucose, which predisposes to severe renal disease.

MODY5 mutations (including deletions, missense and nonsense mutations), are a rare cause of MODY and account for ~1% of all MODY cases