Actin plays a crucial role in diverse physiological processes via the formation of dynamic networks that determine cellular shape and mechanical properties.De novovariants in cytoskeletal β- and γ-actin, encoded by humanACTBandACTG1genes, lead to a wide range of rare diseases, termed Non-Muscle Actinopathies (NMA). Variants include missense, frameshift, truncating variants up to whole gene deletions and induce diverse symptoms. So far, the high clinical variability and genotype-phenotype correlations in NMA remain largely unresolved. To address this question, we used CRISPR to insert in theC. eleganshomologueact-2gene ninede novomutations identified in patients. Using these animal models, we performed a quantitative multiscale characterisation. We uncovered a variety of perturbations: actin network defects at the micro scale, cell scale abnormalities, morphogenesis failure, as well as weaker behavioural phenotypes. Importantly, the range of developmental defects observed correlates with the severity of patients' symptoms. Thus, we provide evidence that aC. elegans-based approach represents a new way to investigate the mechanisms underlying NMA physiopathology or ultimately screen for therapeutic strategies.