CAPRIN1

Inheritance Pattern: AD

Disease ID:MONDO:0957985

Submitter: ClinGen

*CAPRIN1* encodes an mRNA-binding protein that regulates mRNA transport and translation, and plays a role in synaptic plasticity. CAPRIN1 is a component of stress granules and harbors a prion-like domain, like other RNA-binding proteins involved in neurodegenerative disorders. *CAPRIN1* was first reported in relation to autosomal dominant neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline in 2022 (Delle Vedove et al., PMID: 36136249) in two unrelated individuals with the same *de novo* missense variant, p.Pro512Leu. A third individual with the same variant and a similar phenotype was reported in 2025 (PMID: 39878554). The disorder is characterized by the onset of progressive gait and truncal ataxia during childhood (between the ages of 7 and 10), dysarthria, progressive muscle weakness and atrophy, sensorimotor axonal neuropathy, and cognitive decline with learning difficulties. Brain imaging shows cerebellar and cerebral atrophy. The variant exerts a gain-of-function effect by increasing the protein propensity to misfold and aggregate (PMID: 36136249). Of note, *CAPRIN1* haploinsufficiency has been implicated in neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder (PMID: 35979925). This disease assertion was evaluated separately. One recurrent missense variant (p.Pro512Leu) that has been reported in three probands in two publications (PMIDs: 36136249, 39878554) is included in this curation. The variant occurred *de novo* in two individuals, and was absent from the mother in the other one. The mechanism of pathogenicity appears to be gain of function (PMID: 36136249). This gene-disease relationship is also supported by experimental evidence. The p.Pro512Leu variant forms insoluble ubiquitinated aggregates that sequester proteins associated with neurodegenerative disorders, including ATXN2, GEMIN5, and SNCA. iPSC-derived cortical neurons expressing the p.Pro512Leu variant exhibit reduced neuronal activity, reduced RNA affinity, and altered stress granule dynamics. CAPRIN1 is an interacting partner of ATXN2 and GEMIN5, associated with ataxia, and FMR1, associated with fragile X tremor/ataxia syndrome. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. The classification was upgraded from limited to moderate due to the independent occurrence of a recurrent variant in three individuals with a similar phenotype and functional evidence showing a gain-of-function effect. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 18, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0968945

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0968945

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0968945

Submitter: ClinGen

*CAPRIN1* encodes an mRNA-binding protein that regulates mRNA transport, translation and stability, and plays a role in neurogenesis and synaptic plasticity in neurons, and in cell proliferation and migration in multiple cell types. *CAPRIN1* was first reported in relation to autosomal dominant neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder in 2023 (Pavinato et al., PMID: 35979925) in ten unrelated individuals with protein truncating variants (PTVs). Phenotypic features in individuals with *CAPRIN1* haploinsufficiency include language delay and/or speech impairment, intellectual disability (usually mild) or learning disability, autism spectrum disorder (ASD), and attention deficit-hyperactivity disorder. Less common findings include mild limb and/or skeletal anomalies, seizures, and respiratory problems at birth. Of note, a separate clinical entity defined by early onset ataxia and cognitive decline has been described in individuals with a recurrent *de novo* missense variant (p.Pro512Leu) in *CAPRIN1* leading to a gain of function (PMIDs: 36136249, 39878554). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and phenotypic variability between Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder (OMIM: 620782), and Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline (OMIM: 620636). The split curation for autosomal dominant Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline is presented separately. Twenty-two PTVs that have been reported in 22 probands in six publications (PMIDs: 28135719, 31398340, 31981491, 33057194, 35979925, 35982160) are included in this curation. Except for the PTVs reported by Pavinato et al., the other variants were identified in large-scale sequencing studies of neurodevelopmental disorders, with no detailed phenotype information. Twelve PTVs occurred *de novo*, nine were inherited (including one inherited from an affected father), and one was of unknown inheritance. Of note, a sequencing study in over 20,000 ASD individuals identified ten PTVs in *CAPRIN1*; three were *de novo* and seven were inherited from reportedly unaffected parents, including two also present in unaffected siblings (PMID: 35982160). No information was available regarding the phenotype of the transmitting parents. In one family, the paternally inherited variant was present in two siblings with ASD but not in their sister, who was also diagnosed with ASD (PMID: 35982160). *CAPRIN1* PTVs have also been reported in three individuals with schizophrenia and seven controls (PMID: 35396579). Taken together, these findings indicate that *CAPRIN1* haploinsufficiency is associated with incomplete penetrance and/or variable expressivity and additional studies are needed to better understand the phenotypic spectrum. *De novo* missense variants in *CAPRIN1* have been observed in a small number of individuals with developmental disorders (PMID: 33057194) or ASD (PMID: 35982160), but they were not scored due to the lack of supportive functional evidence. *CAPRIN1* is highly constrained for PTVs (pLI 1, LOEUF 0.37, gnomAD v4.1.0), but not for missense variants. The mechanism of pathogenicity is reported to be loss of function (PMID: 35979925). This gene-disease relationship is also supported by experimental evidence, including protein interaction, and cell culture and mouse models (PMIDs: 22737234, 26865403, 29157358, 35979925). In summary, there is moderate evidence to support this gene-disease relationship. The classification was downgraded from strong to moderate due to multiple instances of PTVs inherited from unaffected parents or present in unaffected siblings and controls. More evidence is needed to determine the penetrance and phenotypic spectrum of *CAPRIN1* haploinsufficiency. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 2, 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0957985

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Ambry Genetics