AbstractSub-QTLs and multiple intra-QTL genes are hypothesized to underpin large-effect QTLs. Known QTLs over gene families, biosynthetic pathways or certain traits represent functional gene-clusters of genes of the same gene ontology (GO). Gene-clusters containing genes of different GO have not been elaborated, except in silico as coexpressed genes within QTLs. Here we demonstrate the requirement of multiple intra-QTL genes for the full impact of QTL qDTY_12.1 on rice yield under drought. Multiple evidences are presented for the need of the transcription factor ‘no apical meristem’ (OsNAM_12.1) and its co-localized target genes of separate GO categories for qDTY_12.1 function, raising a regulon-like model of genetic architecture. The molecular underpinnings of qDTY_12.1 support its effectiveness in further improving a drought tolerant genotype and for its validity in multiple genotypes/ecosystems/environments. Resolving the combinatorial value of OsNAM_12.1 with individual intra-QTL genes notwithstanding, identification and analyses of qDTY_12.1has fast-tracked rice improvement towards food security.