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ACTA1 represents one of six highly conserved actin proteins that have all been associated with human disease. The first 15 pathogenic variants in <jats:italic>ACTA1<\/jats:italic> were reported in 1999, which expanded to 177 in 2009. Here, we update on the now 607 total variants reported in LOVD, HGMD, and ClinVar, which includes 343 reported pathogenic\/likely pathogenic (P\/LP) variants. We also provide suggested <jats:italic>ACTA1<\/jats:italic>\u2010specific modifications to ACMG variant interpretation guidelines based on our analysis of known variants, gnomAD reports, and pathogenicity in other actin isoforms. Using these criteria, we report a total of 447 P\/LP <jats:italic>ACTA1<\/jats:italic> variants. From a clinical perspective, the number of reported <jats:italic>ACTA1<\/jats:italic> disease phenotypes has grown from five to 20, albeit with some overlap. The vast majority (74%) of <jats:italic>ACTA1<\/jats:italic> variants cause nemaline myopathy (NEM), but there are increasing numbers that cause cardiomyopathy and novel phenotypes such as distal myopathy. We highlight challenges associated with identifying genotype\u2013phenotype correlations for <jats:italic>ACTA1<\/jats:italic>. Finally, we summarize key animal models and review the current state of preclinical treatments for <jats:italic>ACTA1<\/jats:italic> disease. 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