'single-gene' originates from modern English as a compound of 'single' and 'gene'; 'gene' ultimately derives from Greek 'genos' where 'genos' meant 'birth, race', via late 19th–early 20th century coinage 'gene' (coined c.1909) in genetics.

'single-gene' formed in the 20th century alongside advances in genetics; phrases such as 'single-gene trait' and 'single-gene disorder' appeared in scientific literature and the hyphenated compound 'single-gene' became a concise technical term.

Initially used to indicate that a characteristic involved one gene (often in Mendelian contexts); over time it has remained consistent and is now a standard descriptor for monogenic phenomena.