Abstract Background Point-of-care ultrasonography (POCUS) enables access to cardiac imaging directly at the bedside but is limited by brief acquisition, variation in acquisition quality, and lack of advanced protocols. Purpose To develop and validate deep learning models for detecting underdiagnosed cardiomyopathies on cardiac POCUS, leveraging a novel acquisition quality-adapted modeling strategy. Methods To develop the models, we identified transthoracic echocardiograms (TTEs) of patients across five hospitals in a large U.S. health system with transthyretin amyloid cardiomyopathy (ATTR-CM, confirmed by Tc99m-pyrophosphate imaging), hypertrophic cardiomyopathy (HCM, confirmed by cardiac magnetic resonance), and random controls from the same period enriched for the presence of severe AS. In a sample of 290,245 TTE videos, we used novel augmentation approaches and a customized loss function to weigh image and view quality to train a multi-label, view agnostic video-based convolutional neural network (CNN) to discriminate the presence of ATTR-CM, HCM, and/or AS+ and AS- controls. Models were tested across 3,758 real-world POCUS videos from 1,879 studies in 1,330 independent emergency department (ED) patients from 2011 through 2023 (A). Results Our multi-label, view-agnostic classifier demonstrated state-of-the-art performance in discriminating ATTR-CM (AUROC 0.98 [95%CI: 0.96-0.99]) and HCM (AUROC 0.95 [95% CI: 0.94-0.96]) on standard TTE studies. Automated metrics of anatomical view correctness confirmed significantly lower quality in POCUS vs TTE videos (median view classifier confidence of 0.63 [IQR: 0.44-0.88] vs 0.93 [IQR: 0.69-1.00], p<0.001). When deployed to POCUS videos, our algorithm effectively discriminated ATTR-CM and HCM with AUROC of up to 0.94 (parasternal long-axis (PLAX)), and 0.85 (apical 4 chamber (A4C)) (B), corresponding to positive diagnostic odds ratios of 46.7, and 25.5, respectively. In total, 18/35 (51.4%) of ATTR-CM and 32/57 (41.1%) of HCM patients in the POCUS cohort had a positive AI screen in the year before their eventual confirmatory imaging (C). Conclusions We define and validate an AI framework that enables scalable, opportunistic screening of under-diagnosed cardiomyopathies using POCUS.