The arginine-rich protein (ARP) gene was recently cloned and localized to human chromosome band 3p21. Recent reports have suggested that ARP is mutated in a high percentage of different human tumors. We amplified and sequenced the multiple arginine coding area of the ARP gene in primary head and neck, non-small cell lung, and renal cell cancers. We found a high frequency of genetic changes in this region, including a single base pair substitution and deletions of arginine repeats in primary tumors. However, these changes were always present in matched normal controls. Thus, the variations in the ARP trinucleotide repeat region represent normal polymorphisms rather than tumor-specific mutations.