Approaches to functionally interpret disease-associated common noncoding genetic variants are needed. Now, John Stamatoyannopoulos and colleagues report an analysis to determine how genetic variation affects the activity of the CTCF DNA-binding factor (PLoS Genet. 8, e1002599, 2012). The authors mapped CTCF-binding sites across the genome by chromatin immunoprecipitation followed by sequencing (ChIP-seq) in transformed B-lymphoblastoid cells from 12 members of a 3-generation pedigree, and then performed targeted resequencing of these sites to catalog genetic variation. Of 35,709 CTCF-binding sites, 21% contained one or more SNP, and integration of the CTCF-binding and genetic variation data sets yielded 325 sites at which a SNP genotype was associated with a quantitative measure of CTCF occupancy. The majority of SNPs that affected CTCF occupancy were located in regions of protein-DNA contact, but these SNPs represent only a small minority of all SNPs located in regions of CTCF binding, indicating that there is context-dependent buffering of the ability of genetic variation to alter CTCF occupancy. The authors further found that buffering is partly determined by the strength of the CTCF-binding site and by local sequence context. These findings indicate that local context effects will complicate efforts to predict functional effects of noncoding SNPs.