Understanding local population genetics improves variant interpretation in rare genetic disorders

Abstract Exome sequencing in underrepresented populations reveals unique variant spectra that improve interpretation of rare genetic disorders. We introduce IRExom, a registry of over 3,000 exomes from Iranian patients enriched for rare diseases, providing population-specific frequencies and constraint metrics. Comparison with gnomAD highlights thousands of variants absent globally but frequent locally, resolving uncertain variants and uncovering founder effects, advancing equitable genomic medicine.