The spatial arrangement of chromatin in interphase nuclei is non-random and plays a fundamental role in genome function and stability. Recent advance in spatial genomics techniques unveiled that the chromatin spatial arrangement varies substantially from cell to cell, even among cells of a functionally homogeneous population. By introducing an imaging technique based on sequential fluorescence in-situ hybridization and super-resolution microscopy, that trace the chromatin at high-resolution in single nuclei, in combination with a suite of modelling and analysis tools, we proposed that the genome structural variability itself acts as a signature that distinguishes one genomic region from another1. However, the factors that contribute to structural variability and which are the cause and consequences of structural variability in the context of genome function remain unclear. Here, will aim at lying the biological and computational foundations to understand and quantify the role of structural variability in ensuring a stable genome function, focusing on investigating structural variability signatures that are dependent on cell identity and whereas other component of the nucleus, specifically lncRNAs2, have a role in defying these structural variability signatures. To this end, we will combine imaging techniques, genomic data, structural bioinformatics, and physical theories to investigate the single-cell genome structure at an unprecedented level of detail implementing a set of computational tools for robust quantitative analysis and modelling of spatial genomics data. I envisage that these computational tools will help us and the community to revisit our understanding of genome structure variability within cell subpopulations and tissues establish the foundation to redefine the concept of cell-to-cell genome structure variability open up opening up the possibility to investigate missing links between genome organisation variability and diseases such as developmental disorders and neurological diseases.