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CC2D2A
coiled-coil and C2 domain containing 2A
CC2D2A is located on the short (p) arm of chromosome 4, at band 4p15.32. Arm ratio per GRCh38 - banding schematic.
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Overview
CC2D2A (coiled-coil and C2 domain containing 2A) provides instructions for producing a protein that localises to the base of primary cilia, antenna-like projections on the surface of most cells. Primary cilia serve as signalling hubs, detecting environmental cues and coordinating developmental programmes. The CC2D2A protein participates in ciliogenesis - the process by which cilia assemble and maintain their structure - and regulates the trafficking of proteins into and out of the cilium.
Disruption of CC2D2A function impairs cilia formation and signalling, resulting in a spectrum of ciliopathies characterised by neurological, renal, skeletal, and ocular abnormalities. Because the gene follows autosomal recessive inheritance, carriers with a single pathogenic variant typically remain unaffected, whilst individuals inheriting variants from both parents may develop clinical features.
What the gene does
The CC2D2A protein functions as a scaffolding component at the ciliary transition zone, a specialised region at the base of the cilium that controls which molecules enter or exit the organelle. This gatekeeping role ensures proper compartmentalisation of ciliary signalling pathways, including pathways mediated by Hedgehog and Wnt proteins that are essential for embryonic patterning and tissue development.
CC2D2A interacts with other transition zone proteins to form multiprotein complexes that anchor ciliary membranes and organise the underlying microtubule cytoskeleton. Through these interactions, the protein helps establish the structural foundation required for cilia to project from the cell surface and respond to mechanical or chemical stimuli. Loss of CC2D2A function disrupts this architecture, leading to shortened or absent cilia and consequent failure of developmental signalling cascades in multiple organ systems.
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Chromosome location
CC2D2A resides at chromosomal position 4p15.32 on the short arm of chromosome 4. The genomic locus spans multiple exons, encoding a transcript that directs synthesis of a 1,620-amino-acid protein. This region of chromosome 4 contains several genes involved in developmental processes, though CC2D2A variants segregate independently in families with ciliopathy phenotypes.
Protein structure
The CC2D2A protein comprises 1,620 amino acids organised into functional domains and regions. The N-terminal portion includes a disordered region spanning amino acids 1 to 241, followed by two coiled-coil motifs located at positions 439 to 493 and 532 to 582. These coiled-coil segments mediate protein-protein interactions necessary for assembly of transition zone complexes. A C2 domain occupies amino acids 1,025 to 1,203, a structural module typically involved in calcium-dependent membrane binding or phospholipid recognition. Additional disordered regions are present at positions 592 to 628 and 1,062 to 1,087. The combination of structured domains and flexible linkers allows CC2D2A to function as an adaptable scaffold at the ciliary base.
Key variants
Pathogenic variants in CC2D2A include nonsense, frameshift, and missense changes that reduce or eliminate protein function. Loss-of-function variants are distributed across the gene, with many truncating mutations leading to complete absence of functional protein. Missense variants may disrupt protein interactions or destabilise the folded structure, particularly when they occur within the C2 domain or coiled-coil regions. The specific functional impact of a variant depends on its location and the nature of the amino acid substitution.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.3597_3600del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Meckel-Gruber syndrome |
c.1359+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | CC2D2A-related disorder |
c.1363C>T | p.Gln455Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome |
c.2568del | p.Glu857fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome |
c.2923-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | COACH syndrome 2 |
c.3280del | p.Leu1094fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome |
c.4522dup | p.Ile1508fs | Pathogenic/Likely pathogenic | ★★☆☆ | COACH syndrome 2 |
c.463C>T | p.Gln155Ter | Pathogenic/Likely pathogenic | ★★☆☆ | COACH syndrome 2 |
c.523del | p.Ile175fs | Pathogenic | ★★☆☆ | Joubert syndrome |
c.715del | p.Met239fs | Pathogenic/Likely pathogenic | ★★☆☆ | COACH syndrome 2 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in CC2D2A cause Joubert syndrome, a neurodevelopmental ciliopathy characterised by a distinctive hindbrain malformation called the molar tooth sign, intellectual disability, abnormal breathing patterns, and impaired coordination. Additional features may include retinal dystrophy, kidney cysts, and liver fibrosis. The severity and range of clinical manifestations vary among affected individuals, reflecting the gene's broad role in ciliary function across multiple tissues. Some individuals present with overlapping features of related ciliopathies, underscoring the genetic and phenotypic heterogeneity within this group of conditions.
Inheritance pattern
Conditions caused by pathogenic CC2D2A variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CC2D2A appears on multiple NHS Genomic Medicine Service gene panels with green classification, indicating strong evidence for clinical validity. The gene is included in panels for neurological ciliopathies, rare multisystem ciliopathy disorders, renal ciliopathies, and ophthalmological ciliopathies, reflecting the multisystem nature of associated conditions. It also features in panels for intellectual disability, early onset or syndromic epilepsy, foetal anomalies, hydrocephalus, retinal disorders, structural eye disease, and skeletal dysplasia. This breadth of panel membership supports the use of CC2D2A in diagnostic testing for individuals presenting with features consistent with ciliopathy syndromes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a CC2D2A variant?
A carrier possesses one pathogenic variant in CC2D2A and one typical copy. Carriers generally do not develop symptoms because the functional copy compensates. If two carriers have children together, each pregnancy carries a 25% chance of inheriting both variants and being affected.
How is CC2D2A-related Joubert syndrome diagnosed?
Diagnosis involves clinical assessment, brain imaging to identify the molar tooth sign, and genetic testing to confirm biallelic pathogenic variants in CC2D2A. Additional evaluations may assess kidney, liver, and retinal function.
Are all CC2D2A variants equally severe?
No. The impact depends on the variant type and location. Complete loss-of-function variants typically result in more severe phenotypes, whilst some missense variants may retain partial activity and associate with milder features.