Acid sphingomyelinase (ASM; HGMW-approved symbol, SMPD1) is the lysosomal phosphodiesterase that hydrolyzes sphingomyelin to ceramide and phosphocholine. The deficient activity of this enzyme results in Types A and B Niemann-Pick disease (NPD). The full-length cDNA encoding human ASM has been isolated and characterized (E. H. Schuchman, M. Suchi, T. Takahashi, K. Sandhoff, and R. J. Desnick (1991) J. Biol. Chem. 66:8531-8539), and the ASM gene has been localized to chromosomal region 11p15.1-p15.4 (L. V. Pereira, R. J. Desnick, D. Adler, C. M. Disteche, and E. H. Schuchman (1991) Genomics 9:229-234). Using the cDNA as a probe, a genomic clone containing the ASM genomic region was isolated and the complete nucleotide sequence of the human ASM gene, including 1116 and 468 nucleotides upstream and downstream from the ASM coding region, respectively, was determined. This housekeeping gene contained six exons ranging in size from 77 to 773 bp and five introns ranging in size from 153 to 1059 bp. Exon 2 was unusually large and encoded 258 amino acids, or about 44% of the mature ASM polypeptide. The alternatively spliced 172-bp type 1-specific sequence was encoded by exon 3, whereas the type 2-specific sequence was located at the 5' end of intron 2. An analysis of the intron/exon junctions revealed that there was a weak donor splice site (AAA gtgagg) at the exon 3/intron 3 junction which occasionally leads to alternative splicing of exon 3 and the occurrence of the type 2 and 3 ASM transcripts. A single Alu1 element in the reverse orientation was in intron 2, immediately downstream from the type 2-specific sequence.(ABSTRACT TRUNCATED AT 250 WORDS)