Population differences in allele frequencies modify the clinical interpretation of genetic variants associated with rare diseases in Chilean patients

Background Accurate interpretation of genetic variants relies heavily on population allele frequencies derived from large international reference databases. However, these resources largely underrepresent Latin American populations, raising concerns about the generalizability of variant interpretation and the potential for diagnostic inequities, particularly in admixed and indigenous populations. Here, we evaluated how population-specific allele frequencies influence the clinical interpretation of variants associated with rare diseases in Chilean patients. Results We generated a pilot exomic allele frequency dataset from 60 Chilean individuals without rare diseases and systematically compared it with major international reference databases. Among the 252,169 variants identified, 73,608 were rare or of low frequency in international datasets, of which 10,417 (14.2%) were common in the Chilean population. In addition, 6,043 variants were absent from all the international databases analyzed. Using Chilean allele frequencies as a population reference in standard variant interpretation workflows led to the reclassification of 364 nonbenign variants toward benignity in a cohort of 41 patients with suspected rare diseases. Importantly, two pathogenic and two likely pathogenic variants were reclassified as benign, modifying the diagnostic interpretation in six patients and directly impacting the clinical reports returned to the treating physicians. Conclusions Population-specific genomic diversity significantly influences the clinical interpretation of exome sequencing data. The systematic underrepresentation of Latin American populations in global reference databases can negatively affect diagnostic accuracy and equity in genomic medicine. Our results demonstrate that even pilot population-specific datasets can substantially improve variant classification and support more accurate and equitable genetic diagnoses in underrepresented populations.