Dynamic chromatin organization instantly influences DNA accessibility through modulating local macromolecular density and interactions, driving changes in transcription activities. Chromatin dynamics have been reported to be locally confined but contribute to coherent chromatin motion across the entire nucleus. However, the regulation of dynamics, nuclear orientation and compaction of subregions along a single chromosome are not well-understood. We used CRISPR-based real-time single-particle tracking and polymer models to characterize the dynamics of specific genomic loci and determine compaction levels of large human chromosomal domains. Our studies showed that chromosome compaction changed during interphase and that compactions of two arms on chromosome 19 were different. The dynamics of genomic loci were subdiffusive and dependent on chromosome regions and transcription states. Surprisingly, the correlation between locus-dependent nuclear localization and mobility was negligible. Strong tethering interactions detected at the pericentromeric region implies local condensation or associations with organelles within local nuclear microenvironments, such as chromatin–nuclear body association. Based on our findings, we propose a ‘guided radial model’ for the nuclear orientation of the long arm of chromosome 19.