ARPP21

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

*ARPP21* was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) in 2019 (Cooper-Knock et al., PMID: 30811981). In humans, ARPP21 was initially identified as a 9.6 kDa protein that regulates calcium/calmodulin-dependent signaling (Rakhilin et al., PMID 15499021). A long isoform of ARPP21 appears to function in post-transcriptional regulation of gene expression (Rehfeld et al., PMID 29581509, Halbout et al., PMID 37507022). Nine missense variants that have been reported in 17 probands in four publications (PMIDs: 30811981, 31653410, 35525134, 38960585) are included in this curation. The mechanism of pathogenicity is unknown. This gene-disease association is also supported by expression studies and *in vitro* functional assays (PMIDs: 8120638, 29581509). ARPP21 is predominantly expressed in a subset of brain tissues (PMID 8120638). Endogenous ARPP21 in cultured mouse cortical neurons localizes to stress granules after arsenite treatment (PMID 29581509). This gene-disease pair was originally evaluated by the Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on January 10, 2023. It was reevaluated on January 14, 2025. As a result of this reevaluation, the classification did not change. New evidence was added to the curation, but it was not strong enough to change the classification. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on the meeting date January 14, 2025 (SOP Version 11).