Histidine-rich calcium binding protein (HRC) is a luminal sarcoplasmic reticulum (SR) protein of 165 kDa identified by virtue of its ability to bind 125I-labeled low-density lipoprotein with high affinity after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Hofmann et al., J. Biol. Chem. 264: 8260-8270, 1989). Its role in SR function is unknown. In this report, the gene encoding human HRC was localized to human chromosome 19 and mouse chromosome 7 by hybridization of a human HRC cDNA fragment to a panel of somatic cell hybrids. Known synteny between a portion of human chromosome 19 and a portion of mouse chromosome 7 and in situ hybridization of a biotin-labeled HRC probe to human chromosomes suggest a localization to a region corresponding to 19q13.3. The locus for myotonic dystrophy resides in the region 19q13.2-13.3. Therefore, we considered HRC, a muscle-specific gene, to possibly represent a "candidate gene" for myotonic muscular dystrophy. As a first step toward localizing HRC in relation to the myotonic dystrophy locus, we report the cloning of the human HRC gene, its intron-exon organization, and characterization of several informative polymorphisms to be used in future linkage studies in families with myotonic dystrophy. Of particular interest is an Alu-associated poly-d(GA) sequence located in an intron in the middle of the gene, and two stretches of acidic amino acids in the coding region of exon 1 that vary in length among different individuals.