SCAPER

Inheritance Pattern: AR

Disease ID:MONDO:0032594

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032594

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032594

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0032594

Submitter: ClinGen

Biallelic pathogenic variants in the *SCAPER* gene were first reported in 2017 in association with autosomal recessive neurodevelopmental disorder with retinitis pigmentosa, sometimes referred to as SCAPER-related intellectual disability–retinal dystrophy syndrome (PMID: 28041643, PMID: 28794130). Affected individuals typically present with developmental delay or intellectual disability, behavioral abnormalities, short stature, and progressive retinal degeneration leading to night blindness and visual field constriction. The retinal phenotype is a consistent and defining feature but can vary in onset and severity (PMID: 28794130, PMID: 30723319; PMID: 31192531). In contrast, intellectual disability and neurodevelopmental features, although frequently co-occurring, show greater phenotypic variability and broader tissue involvement, suggesting pleiotropic effects. Functional studies demonstrate that disease-causing *SCAPER* variants disrupt ciliary dynamics, leading to abnormal cilia elongation—an established pathogenic mechanism in inherited retinal dystrophies. Therefore, for the purposes of this gene curation, *SCAPER* has been evaluated in relation to *SCAPER*-related ciliopathy. To date, multiple loss-of-function variants have been identified in affected individuals, including frameshift, nonsense, splice-site variants (PMID: 28794130). The spectrum of pathogenic variants and the available functional data strongly support loss of function as the primary disease mechanism for *SCAPER*-related disease. Functional studies in patient-derived fibroblasts and transfected cell lines demonstrated that mutant SCAPER proteins show abnormal localization to the primary cilium, particularly at the ciliary tip, in contrast to wild-type SCAPER, which is rarely detected along the ciliary axoneme. Cells expressing mutant SCAPER exhibited elongated cilia, suggesting impaired ciliary disassembly. These findings implicate SCAPER in ciliary dynamics and link its dysfunction to retinal degeneration and neurodevelopmental phenotypes, consistent with a ciliopathy-like mechanism (PMID: 28794130, PMID: 30723319). This gene-disease relationship is further supported by experimental evidence that SCAPER (S-phase Cyclin A–Associated Protein in the ER) encodes a large nuclear and cytoplasmic protein involved in cell cycle regulation and ciliary dynamics. SCAPER was originally identified as a cyclin A–interacting protein, with expression peaking during late G1 and S phase, suggesting a role in S-phase progression and mitotic regulation (PMID: 28794130, PMID: 30723319). *SCAPER* is ubiquitously expressed across a wide range of human tissues, including retina and brain. SCAPER is robustly expressed in the retina, where it localizes predominantly to the cytoplasm of retina cells, and is detected across multiple retinal layers, with highest expression in the retinal pigment epithelium and in photoreceptor inner and outer segments (PMID: 28794130, PMID: 30723319). In summary, *SCAPER* is Definitively associated with *SCAPER*-related ciliopathy. This has been repeatedly demonstrated across multiple studies in both the research and clinical diagnostic settings and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the ClinGen Retina gene Curation Expert Panel on January 15th, 2026 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia