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10 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
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CCDC22
CCC complex scaffolding subunit CCDC22
Chromosome X Β· Xp11.23
NCBI Gene: 28952Ensembl: ENSG00000101997.14HGNC: HGNC:28909UniProt: O60826
71PubMed Papers
21Diseases
0Drugs
3Pathogenic Variants
FUNCTIONAL ROLE
Highly ConstrainedTransporter
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
cullin family protein bindingcentrosomeintracellular copper ion homeostasisGolgi to plasma membrane transport3C syndromeneurodegenerative diseaseX-linked syndromic intellectual disabilityX-linked non-syndromic intellectual disability
✦AI Summary

CCDC22 is a key scaffolding subunit of the CCC (CCDC22/CCDC93/COMMD) complex, which is essential for endosomal recycling of transmembrane proteins back to the cell surface 1. The protein forms a coiled-coil structure that connects the CCC assembly with the Retriever complex (VPS35L, VPS26C, VPS29) to create the complete Commander complex, a 16-protein assembly involved in endosomal cargo retrieval 1. CCDC22 stabilizes a hetero-decameric ring of COMMD proteins through extensive interactions and recruits DENND10 to complete the complex 1. This machinery prevents lysosomal degradation and promotes recycling of over 120 cell surface proteins, including integrins, signaling receptors, and solute transporters 2. The Commander complex also regulates lysosomal homeostasis and has been implicated in Parkinson's disease risk 3. Mutations in CCDC22 cause X-linked Ritscher-Schinzel syndrome 2, a rare developmental disorder characterized by craniofacial dysmorphism, cerebellar malformations, cardiovascular defects, and intellectual disability 4. Specific missense mutations that disrupt COMMD protein binding result in attenuated forms of the syndrome without cardiac or neuroanatomical abnormalities 5. The complex also plays roles in cilium assembly, centrosome function, and copper homeostasis 6.

Sources cited
1
CCDC22 is a scaffolding subunit of the CCC complex that forms coiled-coil structures connecting CCC and Retriever assemblies
PMID: 37172566
2
The retriever-CCC pathway prevents lysosomal degradation and promotes recycling of over 120 cell surface proteins
PMID: 28892079
3
Commander complex regulates lysosomal homeostasis and is implicated in Parkinson's disease risk
PMID: 40209002
4
CCDC22 mutations cause X-linked Ritscher-Schinzel syndrome 2 with craniofacial, cerebellar, and cardiac features
PMID: 36130690
5
Specific CCDC22 mutations that impair COMMD binding cause attenuated syndrome forms
PMID: 40448120
6
Commander complex has roles in cilium assembly, centrosome and centriole functions
PMID: 38459129
Disease Associationsβ“˜21
3C syndromeOpen Targets
0.67Moderate
neurodegenerative diseaseOpen Targets
0.55Moderate
X-linked non-syndromic intellectual disabilityOpen Targets
0.46Moderate
X-linked syndromic intellectual disabilityOpen Targets
0.46Moderate
syndromic intellectual disabilityOpen Targets
0.37Weak
lysosomal storage diseaseOpen Targets
0.36Weak
Intellectual disabilityOpen Targets
0.12Weak
immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndromeOpen Targets
0.12Weak
Ritscher-Schinzel syndromeOpen Targets
0.01Suggestive
endometriosisOpen Targets
0.01Suggestive
systemic juvenile idiopathic arthritisOpen Targets
0.01Suggestive
neoplasmOpen Targets
0.01Suggestive
hemophagocytic syndromeOpen Targets
0.01Suggestive
cancerOpen Targets
0.01Suggestive
HypercholesterolemiaOpen Targets
0.01Suggestive
aggressive NK-cell leukemiaOpen Targets
0.01Suggestive
autoimmune diseaseOpen Targets
0.01Suggestive
Focal cortical dysplasiaOpen Targets
0.01Suggestive
genetic disorderOpen Targets
0.01Suggestive
systemic lupus erythematosusOpen Targets
0.01Suggestive
Ritscher-Schinzel syndrome 2UniProt
Pathogenic Variants3
NM_014008.5(CCDC22):c.1273C>T (p.Arg425Trp)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 425
NM_014008.5(CCDC22):c.1670A>G (p.Tyr557Cys)Pathogenic
Ritscher-Schinzel syndrome 2|Ritscher-Schinzel syndrome 1
β˜†β˜†β˜†β˜†2015β†’ Residue 557
NM_014008.5(CCDC22):c.49A>G (p.Thr17Ala)Pathogenic
Ritscher-Schinzel syndrome 2|Ritscher-Schinzel syndrome 1
β˜†β˜†β˜†β˜†2012β†’ Residue 17
View on ClinVar β†—
Related Genes
COMMD3Protein interaction100%COMMD9Protein interaction97%WASHC2CProtein interaction96%COMMD2Protein interaction91%COMMD4Protein interaction91%COMMD10Protein interaction88%
Tissue Expression6 tissues
Lung
100%
Liver
86%
Bone Marrow
86%
Ovary
85%
Heart
71%
Brain
56%
Gene Interaction Network
Click a node to explore
CCDC22COMMD3COMMD9WASHC2CCOMMD2COMMD4COMMD10
PROTEIN STRUCTURE
Preparing viewer…
PDB8P0W Β· 2.90 Γ… Β· EM
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.17Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.08 [0.04–0.17]
RankingsWhere CCDC22 stands among ~20K protein-coding genes
  • #6,616of 20,598
    Most Researched71
  • #4,031of 5,498
    Most Pathogenic Variants3
  • #304of 17,882
    Most Constrained (LOEUF)0.17 Β· top 5%
Genes detectedCCDC22
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome.
PMID: 37172566
Cell Β· 2023
1.00
2
Commander complex regulates lysosomal function and is implicated in Parkinson's disease risk.
PMID: 40209002
Science Β· 2025
0.90
3
Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes.
PMID: 36130690
Eur J Med Genet Β· 2022
0.80
4
Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling.
PMID: 28892079
Nat Cell Biol Β· 2017
0.70
5
Structure and interactions of the endogenous human Commander complex.
PMID: 38459129
Nat Struct Mol Biol Β· 2024
0.60