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Bulk sequencing of tissues captures mutation frequencies but cannot reconstruct clonal architectures nor delineate how driver mutations affect cellular phenotypes. We developed single-cell genotype-to-phenotype sequencing (scG2P) for high-throughput, highly multiplexed, joint capture of genotyping of mutation hotspots and mRNA markers. We applied scG2P to aged esophagus samples from six individuals and observed large numbers of clones with a single driver event, accompanied by rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, whereas TP53 mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high-resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Joint single-cell capture of somatic mutations and mRNA transcripts reconstructs clonal architecture and associated phenotypes of the phenotypically normal esophagus, providing the first single-cell genotype\u2013phenotype map of this clonally mosaic tissue to accelerate our understanding of human somatic evolution in solid tissues and provide a window into early cancerous states.<\/jats:p>\n                  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