East Asians are featured with the EDAR V370A mutation, which resides on 2q12.3, and this mutation is believed to be underlying recent selection. However, the genetic architecture and functional stratification of this region have not yet been well documented. Here, using analysis of data from the 1000 Genomes Project, archaic genomes, and blood single-cell RNA-seq, we explore the evolutionary forces that shape the genetic diversity of this locus and attempt to elucidate their functional impacts. Notably, 14 variants closely linked in chr2:108300000-108920000, including the EDAR V370A variant, were observed to be under strong selection (allele frequency is ~0.9 in EAS, 0.3 in AMR, and 0 in other populations). Among the 6 major haplotype groups identified in KGP, the one harboring these 14 East-Asian-specific alleles is most closely related to a haplotype prevalent in Eurasia. We further analyzed public gene expression data and found an increased frequency of alleles with up-regulating effects for GCC2 and LIMS1. Moreover, we observed the cell-type specific expression pattern for GCC2 and LIMS1 in lymphocytes, and the expression of LIMS1 and GCC2 is related to the immune response to virus infection. Nonetheless, none of these highly selected 14 loci were cis-eQTLs for genes in this region. Through prediction, we identified 2 loci with altered transcription factor binding specificity and may exert regulatory functions undetected for LIMS1. We further investigated the pleiotropic effects associated with 2q12.3 and the selection event, finding various aspects of the immune functions of this locus, including infection, cancer, inflammation, and transplantation rejection. We propose that this selection event alters the immune property, through modulating the expression level of GCC2 and LIMS1. Our analysis provided new insights into the evolutionary mechanism of this locus, as well as hints at functional stratification and medical implications.