Work

Population-specific differences in ClinVar pathogenic and likely pathogenic variants of epilepsy-associated genes between East Asian and non-finnish European populations: a nucleotide-resolved gnomAD v4.1.1 analysis

Year: 2026

Type: article

Abstract: Pathogenic and likely pathogenic (P/LP) variants in ClinVar guide variant interpretation in clinical genetic testing, yet their population-specific frequency differences have not been systematically examined in epilepsy. We compiled 199 epilepsy-associated genes, extracted 46,746 unique P/LP variants from ClinVar, and retrieved allele frequencies from gnomAD v4.1.1 gene-level tables using nucleotide-resolved matching. Fisher’s exact test with Benjamini-Hochberg correction (q < 0.05) identified nine variants significantly enriched in East Asian (EAS) relative to non-Finnish European (NFE) populations, with odds ratios of 36.3–867.9. Eight additional low-frequency EAS signals met the same enrichment criterion with at least two EAS alleles and an uncorrected p < 0.01 and are reported as exploratory. Thirteen of the seventeen variants reside in seven autosomal recessive genes, namely, ALDH7A1 , ST3GAL5 , GOSR2 , AARS1 , BRAT1 , WWOX , and UBA5 . In parallel, an rsID-level workflow, the standard approach in database mining, yielded 60 candidate EAS-enriched variants. Nucleotide-resolved matching confirmed only fifteen of these and additionally recovered two signals the rsID workflow missed, a false-positive rate of 75.0%. These findings show that epilepsy P/LP variant frequencies differ substantially between EAS and NFE populations and concentrate in recessive genes with direct relevance to carrier screening. rsID-level ClinVar-gnomAD integration systematically overestimates population specificity, and nucleotide-resolved allele matching should become a standard step in population frequency analyses.

Source: Frontiers in Genetics

DOI: 10.3389/fgene.2026.1973684

Authors: Jin-Xing Lai, Ming-Feng He, Zhi-Cong Fan, Fu-Jiang Yan, Bao-Zhu Guan, Xiang-Hong Liu