LeCellModel: Interpretable Density Estimation over the Gene Expression Manifold

Representation learning for single-cell RNA-seq has been evaluated by the identities representations capture — cell types, lineages, perturbations — rather than how faithfully they model the distribution of cell states on the gene expression manifold. As a result, density estimation, rare-state detection, perturbation scoring, and gene-level attribution are bolted onto frozen embeddings as separate models, disconnected from the geometry of the data. We argue that the density model should be the primary object and that representation quality follows from it. Building on LeJEPA, whose SIGReg objective enforces a provably optimal isotropic Gaussian latent, we introduce LeCellModel, which exploits this Gaussian latent to recover data density on the gene expression manifold via the encoder's Jacobian log-volume (JEPA-SCORE). Across several datasets, LeCellModel outperforms established methods on scIB benchmark for representation quality. Furthermore, we show that LeCellModel enables estimation of rare expression states using JEPA-SCORE as a typicality measure – applying it to a controlled cytokine panel, where it identifies stimulated cells across minority fractions and tracks pathway-response magnitude. We introduce gene-level interpretability of density estimates — to our knowledge, the first method for analyzing JEPA-SCORE in feature space. Leveraging this framework, LeCellModel recapitulates the known association of a profibrotic macrophage program with idiopathic pulmonary fibrosis, and discovers a novel CD177$^{+}$ activated regulatory T cell subpopulation previously described only in tumor contexts. Both findings emerge directly from the geometry of the learned embedding, without relying on supervised annotations.