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

In 199 Lebanese adults aged 65–91, gnomAD Middle Eastern reference size missed cohort alleles no more often than half the cohort missed the other half (ratio 0.98).

• Why it matters: Claims that variants absent from gnomAD reflect unique variation in underrepresented groups can be confounded by reference-size effects, complicating variant interpretation.
• What they did: The study reanalyzed exomes from 199 Lebanese adults and compared allele absence against a size-matched test, then calibrated clonal hematopoiesis filtering using an in-callset allele-fraction background.
• The result: Excess absence was limited to recurrent alleles, while regional disease alleles like MEFV p.Val726Ala were fourfold enriched; calibrations classified 5 of 12 clonal hematopoiesis candidates as probable.

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