Founder alleles and clonal hematopoiesis, not missing diversity, confound variant interpretation in an underrepresented population

Variants absent from gnomAD are widely cited as evidence of unique variation in underrepresented populations, but absence also depends on reference size. We reanalyzed exomes from 199 Lebanese adults aged 65-91 years, to our knowledge the first Levantine cohort not ascertained for genetic disease; 14.6% had first-cousin-level autozygosity. Although 13.8% of alleles were absent from the gnomAD Middle Eastern group, nine times more than a sampling model predicted, a size-matched test showed that this reference missed cohort alleles no more often than one half of the cohort missed the other half (ratio 0.98). Excess absence was confined to recurrent alleles, and population differences concentrated in regional disease alleles such as MEFV p.Val726Ala (fourfold enriched). An in-callset allele-fraction background classified only 5 of 12 clonal hematopoiesis candidates as probable and kept a blood-detected TP53 frameshift out of germline findings. These calibrations generalize to other underrepresented and aging cohorts.