Interrogation of the Human Genome data for sequences related to the von Willebrand factor A-domain module identified a previously unreported 4.1 kb full-length cDNA that is predicted to encode a new member of the collagen superfamily of extracellular matrix proteins, collagen XXI. The domain organization of collagen XXI comprised an N-terminal signal sequence, followed by single von Willebrand factor A-domain and thrombospondin domains, and an interrupted collagen triple helix. The organization of these motifs predict that collagen XXI is a new member of the FACIT collagen sub-family. Expression analysis indicated that COL21A1 mRNA is present in many tissues including heart, stomach, kidney, skeletal muscle and placenta, and radiation hybrid mapping localized the COL21A1 gene to 6p11-12.