摘要: Recent advancements in genome sequencing have enabled the estimation of genetic load through deleterious mutation profiling. However, Chinese populations remain underexplored in this context. We analyze whole-exome sequencing data from 5002 individuals, encompassing major Han subgroups—North Han (N-Han), South Han (S-Han), and Guangxi Han (G-Han)—as well as 13 ethnic minorities. Notably, G-Han exhibits significant genetic affinity with the Zhuang population. Systematic curation of 2110 ClinVar pathogenic or likely pathogenic variants reveals 93.4% are ultra-rare. Exceptions include GJB2 rs72474224-A (hearing loss), which shows higher frequencies in Zhuang and G-Han, and β-thalassemia-associated HBB variants (rs33986703-A and rs33950507-T), which are elevated in G-Han compared to other Han subgroups. Among 96 autosomal dominant mutation carriers, LDLR variants are predominant (∼25%), with comparable frequencies across Han subgroups. Adaptive signatures highlight gene-environment interactions: MTHFR rs1801133-A (UV adaptation) declines southward, while ALDH2 rs671-A (alcohol metabolism) displayed the opposite trend. ABCC11 rs17822931-A, associated with tropical adaptation, is particularly prevalent in G-Han. Gene-based rare-variant collapsing analyses identify an elevated risk of retinitis pigmentosa in S-Han (PRPF4, TUB). Our findings demonstrate that genetic load in Chinese populations is influenced by demographic history, population structure, and regional adaptation, emphasizing the importance of population-specific frameworks in precision medicine.