Neurodegenerative disorders, adult onset

Gene: ARPP21

I don't know

Comment on list classification: There are two independent large-scale genetic studies (PMIDs: 38960585 & 41917433) linked ARRP21 to ALS with consistent variants (p.Pro529Leu/ p.Pro563Leu & p.Pro747Leu) and clinical severity, but no functional validation of any disease variant exists, analysis suggested variant embedded in founder-type haplotype and replication failed in Asian/Australian cohorts. ClinGen GCEP has still rated it with 'Limited' evidence, with it's last review on 14 January 2025. Hence, this gene should be rated amber with this evidence.

The 'watchlist' tag has been added to re-review once functional data or a formal GCEP upgrade emerge.

Created: 24 Aug 2026, 10:39 a.m. | Last Modified: 24 Aug 2026, 10:39 a.m.

Panel Version: 9.11

PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177) The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.

PMID:33581934 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes.

PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations.

PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1.

There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons .

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen.
Sources: Literature

Created: 23 Aug 2026, 8:22 p.m. | Last Modified: 24 Aug 2026, 10:29 a.m.

Panel Version: 9.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
amyotrophic lateral sclerosis, MONDO:0004976

Publications

• 8120638
• 29581509
• 30811981
• 31653410
• 33581934
• 38960585
• 41917433