CCDC22

Summary

CCDC22 (CCC complex scaffolding subunit CCDC22, HGNC:28909) is a protein-coding gene on chromosome Xp11.23, encoding Coiled-coil domain-containing protein 22 (O60826). Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the Commander complex is composed of composed of the CCC subcomplex and the retriever subcomplex. It is a selective cancer dependency (DepMap: 10.9% of cell lines).

This gene encodes a protein containing a coiled-coil domain. The encoded protein functions in the regulation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) by interacting with COMMD (copper metabolism Murr1 domain-containing) proteins. The mouse orthologous protein has been shown to bind copines, which are calcium-dependent, membrane-binding proteins that may function in calcium signaling. This human gene has been identified as a novel candidate gene for syndromic X-linked intellectual disability.

Source: NCBI Gene 28952 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ritscher-Schinzel syndrome 2 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 262 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 90
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.9% of screened cell lines
• MANE Select transcript: NM_014008

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28909
Approved symbol	CCDC22
Name	CCC complex scaffolding subunit CCDC22
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	JM1
Ensembl gene	ENSG00000101997
Ensembl biotype	protein_coding
OMIM	300859
Entrez	28952

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 17 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000376227, ENST00000490300, ENST00000496651, ENST00000904953, ENST00000904954, ENST00000904955, ENST00000904956, ENST00000904957, ENST00000904958, ENST00000904959, ENST00000933905, ENST00000933906, ENST00000933907, ENST00000933908, ENST00000960400, ENST00000960401, ENST00000960402, ENST00000960403, ENST00000960404

RefSeq mRNA: 1 — MANE Select: NM_014008 NM_014008

CCDS: CCDS14322

Canonical transcript exons

ENST00000376227 — 17 exons

Exon	Start	End
ENSE00000670092	49249651	49249725
ENSE00000670093	49249509	49249568
ENSE00000670095	49249167	49249262
ENSE00000670097	49248817	49248924
ENSE00000670099	49248633	49248734
ENSE00000670106	49247649	49247768
ENSE00000670108	49247496	49247558
ENSE00000670110	49246731	49246925
ENSE00000670113	49243284	49243462
ENSE00001469808	49250148	49250520
ENSE00001841978	49235470	49235686
ENSE00003471763	49242016	49242148
ENSE00003490596	49243118	49243184
ENSE00003518171	49248191	49248310
ENSE00003532933	49248407	49248523
ENSE00003533836	49242886	49242992
ENSE00003552859	49237086	49237263

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 90.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.7456 / max 126.4349, expressed in 1812 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196329	11.2353	1807
196328	6.5103	1756

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	90.50	gold quality
monocyte	CL:0000576	86.89	gold quality
leukocyte	CL:0000738	86.80	gold quality
mononuclear cell	CL:0000842	86.74	gold quality
mucosa of transverse colon	UBERON:0004991	85.90	gold quality
apex of heart	UBERON:0002098	85.61	gold quality
tendon of biceps brachii	UBERON:0008188	85.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.03	gold quality
gastrocnemius	UBERON:0001388	84.98	gold quality
spleen	UBERON:0002106	84.96	gold quality
blood	UBERON:0000178	84.60	gold quality
muscle of leg	UBERON:0001383	84.41	gold quality
cerebellar hemisphere	UBERON:0002245	84.34	gold quality
parotid gland	UBERON:0001831	84.30	gold quality
cerebellar cortex	UBERON:0002129	84.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.01	gold quality
cerebellum	UBERON:0002037	83.16	gold quality
body of stomach	UBERON:0001161	83.08	gold quality
lower esophagus mucosa	UBERON:0035834	83.04	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	82.91	silver quality
right adrenal gland	UBERON:0001233	82.71	gold quality
right coronary artery	UBERON:0001625	82.71	gold quality
right adrenal gland cortex	UBERON:0035827	82.40	gold quality
left adrenal gland	UBERON:0001234	82.33	gold quality
skin of leg	UBERON:0001511	82.26	gold quality
lower esophagus	UBERON:0013473	82.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.26	gold quality
esophagus mucosa	UBERON:0002469	82.22	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.16	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting CCDC22, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-450B-3P	97.56	66.12	512
HSA-MIR-6802-3P	97.29	65.42	613
HSA-MIR-769-3P	97.06	64.83	464
HSA-MIR-3654	96.43	66.55	646
HSA-MIR-658	88.20	67.03	178

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Identifies the homologous mouse protein as a copine-binding protein. (PMID:12522145)
• This study demonistrated that CCDC22 is a novel candidate gene for syndromic X-linked intellectual disability. (PMID:21826058)
• CCDC22 participates in NF-kappaB activation and its deficiency leads to decreased IkappaB turnover (PMID:23563313)
• Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome (PMID:24916641)
• CCDC22 mutation is associated with hypercholesterolemia. (PMID:26965651)
• Our results suggest that rs2294020 is associated with the risk of several autoimmune diseases in European populations, specifically with diseases that present themselves, among else, in the skin. (PMID:27888057)
• SNPs within the CCDC22 gene are associated with increased susceptibility to endometriosis in Brazilian women. (PMID:28470452)
• Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes. (PMID:36130690)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccdc22	ENSDARG00000052379
mus_musculus	Ccdc22	ENSMUSG00000031143
rattus_norvegicus	Ccdc22	ENSRNOG00000010846
drosophila_melanogaster	CG9951	FBGN0036671
caenorhabditis_elegans		WBGENE00019959

Protein

Protein identifiers

Coiled-coil domain-containing protein 22 — O60826 (reviewed: O60826)

All UniProt accessions (1): O60826

UniProt curated annotations — full annotation on UniProt →

Function. Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the Commander complex is composed of composed of the CCC subcomplex and the retriever subcomplex. Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels. Involved in regulation of NF-kappa-B signaling. Promotes ubiquitination of I-kappa-B-kinase subunit IKBKB and its subsequent proteasomal degradation leading to NF-kappa-B activation; the function may involve association with COMMD8 and a CUL1-dependent E3 ubiquitin ligase complex. May down-regulate NF-kappa-B activity via association with COMMD1 and involving a CUL2-dependent E3 ubiquitin ligase complex. Regulates the cellular localization of COMM domain-containing proteins, such as COMMD1 and COMMD10. Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels. The CCC complex associates with SNX17, retriever and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of numerous cargos such as integrins ITGA5:ITGB1. Plays a role in copper ion homeostasis. Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes. (Microbial infection) The CCC complex, in collaboration with the heterotrimeric retriever complex, mediates the exit of human papillomavirus to the cell surface.

Subunit / interactions. Component of the commander complex consisting of the CCC subcomplex and the retriever subcomplex. Component of the CCC (COMMD/CCDC22/CCDC93) subcomplex consisting of COMMD1, COMMD2, COMMD3, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8, COMMD9, COMMD10, CCDC22 and CCDC93. Forms a coiled-coil heterodimer with CCDC22; this heterodimer interacts with the guanine nucleotide exchange factor DENND10; the interaction is direct. Interacts with CUL1, CUL2, CUL3, SKP1, BTRC. Interacts with SNX17 and SNX31. Interacts with CPNE1 and CPNE4.

Subcellular location. Endosome. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Widely expressed in adult tissues and in fetal liver and brain, with highest levels in prostate and lowest in skeletal muscle.

Disease relevance. Ritscher-Schinzel syndrome 2 (RTSC2) [MIM:300963] A form of Ritscher-Schinzel syndrome, a developmental malformation syndrome characterized by cerebellar brain malformations, congenital heart defects, and craniofacial abnormalities. RTSC2 is an X-linked recessive form characterized by intellectual disability associated with posterior fossa defects, cardiac malformations, and minor abnormalities of the face and distal extremities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CCDC22 family.

RefSeq proteins (1): NP_054727* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008530	CCDC22	Family
IPR048348	CCDC22_CC	Domain
IPR048349	CCDC22_N	Domain

Pfam: PF05667, PF21674

UniProt features (21 total): helix 9, region of interest 3, sequence variant 3, chain 1, sequence conflict 1, strand 1, coiled-coil region 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8P0W	ELECTRON MICROSCOPY	2.9
8F2U	ELECTRON MICROSCOPY	3.53
8P0V	ELECTRON MICROSCOPY	6.5
8P0X	ELECTRON MICROSCOPY	7.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60826-F1	78.95	0.36

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 410

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 356 (showing top): GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_MICROTUBULE_ORGANIZING_CENTER, EFC_Q6, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_GOLGI_TO_PLASMA_MEMBRANE_TRANSPORT, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, BROWNE_HCMV_INFECTION_14HR_DN, GOCC_CENTROSOME, TGACATY_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (7): intracellular copper ion homeostasis (GO:0006878), Golgi to plasma membrane transport (GO:0006893), protein transport (GO:0015031), endocytic recycling (GO:0032456), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060)

GO Molecular Function (2): cullin family protein binding (GO:0097602), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), endosome (GO:0005768), centrosome (GO:0005813), cytosol (GO:0005829), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
vesicle-mediated transport to the plasma membrane	2
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
intracellular monoatomic cation homeostasis	1
copper ion homeostasis	1
post-Golgi vesicle-mediated transport	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
endosomal transport	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
positive regulation of protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
protein binding	1
binding	1
nuclear lumen	1
endomembrane system	1
cytoplasmic vesicle	1
centriole	1
microtubule organizing center	1
cytoplasm	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1407 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCDC22	CCDC93	Q567U6	998
CCDC22	VPS35L	Q7Z3J2	978
CCDC22	COMMD1	Q8N668	950
CCDC22	VPS26C	O14972	901
CCDC22	COMMD8	Q9NX08	845
CCDC22	COMMD4	Q9H0A8	775
CCDC22	COMMD2	Q86X83	745
CCDC22	COMMD6	Q7Z4G1	730
CCDC22	COMMD3	Q9UBI1	726
CCDC22	SNX17	Q15036	725
CCDC22	COMMD9	Q9P000	677
CCDC22	WASHC2A	Q641Q2	656
CCDC22	VPS29	Q9UBQ0	656
CCDC22	WASHC2C	Q9Y4E1	653
CCDC22	WASHC3	Q9Y3C0	649

IntAct

210 interactions, top by confidence:

A	B	Type	Score
COMMD1	CCDC22	psi-mi:“MI:0914”(association)	0.970
COMMD1	CCDC22	psi-mi:“MI:0915”(physical association)	0.970
CCDC22	COMMD1	psi-mi:“MI:0403”(colocalization)	0.970
CCDC22	COMMD1	psi-mi:“MI:0915”(physical association)	0.970
CCDC22	COMMD1	psi-mi:“MI:0914”(association)	0.970
CCDC22	CCDC93	psi-mi:“MI:0914”(association)	0.960
CCDC93	CCDC22	psi-mi:“MI:0914”(association)	0.960
CCDC93	CCDC22	psi-mi:“MI:0915”(physical association)	0.960
CCDC93	CCDC22	psi-mi:“MI:0407”(direct interaction)	0.960
CCDC22	CCDC93	psi-mi:“MI:0403”(colocalization)	0.960
CCDC22	CCDC93	psi-mi:“MI:0915”(physical association)	0.960

BioGRID (293): CCDC22 (Two-hybrid), USHBP1 (Two-hybrid), CCDC93 (Affinity Capture-Western), C16orf62 (Affinity Capture-Western), CCDC22 (Affinity Capture-Western), CCDC22 (Affinity Capture-Western), CCDC22 (Affinity Capture-MS), CCDC22 (Affinity Capture-MS), CCDC22 (Affinity Capture-MS), CCDC22 (Affinity Capture-MS), CCDC22 (Affinity Capture-MS), CCDC22 (Affinity Capture-MS), CCDC22 (Affinity Capture-MS), CCDC22 (Affinity Capture-MS), ARHGAP1 (Co-fractionation)

ESM2 similar proteins: A0JNG4, A1L3T7, B1AVH7, B5DFA1, D2H0G5, E1U8D0, E9QHE3, I1VZH0, O08629, O60826, O75052, O94964, P58660, P86182, P98171, Q13263, Q149G0, Q1LWB0, Q1RMI8, Q3ULW6, Q3V3A7, Q571B6, Q58D79, Q5JV73, Q5R8S0, Q62318, Q6P4K6, Q6PGG2, Q6ZQ29, Q6ZRF8, Q768S4, Q7TSI1, Q80TQ5, Q8BL43, Q8C7B8, Q8IWE5, Q8K1S6, Q8N163, Q8TF30, Q8VDP4

Diamond homologs: A7RNG8, B0WTU5, O60826, P86182, Q16VW9, Q1RMI8, Q28G12, Q4V909, Q6PA15, Q7PZ96, Q9JIG7, Q8I145, Q8I1C8, Q8I1H7, Q9VVB4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 110 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	5	18.2×	5e-04
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	5	18.2×	5e-04
SCF-beta-TrCP mediated degradation of Emi1	5	17.5×	5e-04
Negative regulation of NOTCH4 signaling	5	17.5×	5e-04
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	5	17.5×	5e-04
NIK–>noncanonical NF-kB signaling	5	16.8×	5e-04
Degradation of GLI1 by the proteasome	5	16.5×	5e-04
Degradation of GLI2 by the proteasome	5	16.5×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	6	17.1×	8e-04
cilium assembly	9	7.0×	2e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	9	5.0×	9e-03
protein transport	10	4.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

262 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	147
Likely benign	38
Benign	8

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
218105	NM_014008.5(CCDC22):c.49A>G (p.Thr17Ala)	Pathogenic
218106	NM_014008.5(CCDC22):c.1670A>G (p.Tyr557Cys)	Pathogenic
979777	GRCh37/hg19 Xp11.23-11.22(chrX:48102202-52685635)x2	Pathogenic
3342749	NM_014008.5(CCDC22):c.1273C>T (p.Arg425Trp)	Likely pathogenic

SpliceAI

2818 predictions. Top by Δscore:

Variant	Effect	Δscore
X:49235687:G:GG	donor_gain	1.0000
X:49242144:TGCAG:T	donor_loss	1.0000
X:49242146:CAGG:C	donor_loss	1.0000
X:49242147:AG:A	donor_loss	1.0000
X:49242148:GGT:G	donor_loss	1.0000
X:49242149:G:T	donor_loss	1.0000
X:49242150:T:G	donor_loss	1.0000
X:49242875:A:AG	acceptor_gain	1.0000
X:49242876:T:G	acceptor_gain	1.0000
X:49242882:A:AG	acceptor_gain	1.0000
X:49242882:ATAG:A	acceptor_gain	1.0000
X:49242883:T:G	acceptor_gain	1.0000
X:49242884:A:AG	acceptor_gain	1.0000
X:49242884:AG:A	acceptor_gain	1.0000
X:49242884:AGGT:A	acceptor_gain	1.0000
X:49242885:G:A	acceptor_gain	1.0000
X:49242885:G:GA	acceptor_gain	1.0000
X:49242885:GGT:G	acceptor_gain	1.0000
X:49242885:GGTG:G	acceptor_gain	1.0000
X:49242885:GGTGA:G	acceptor_gain	1.0000
X:49242989:CCAGG:C	donor_loss	1.0000
X:49242990:CAGG:C	donor_loss	1.0000
X:49242991:AGG:A	donor_loss	1.0000
X:49242992:GGTGA:G	donor_loss	1.0000
X:49242993:G:A	donor_loss	1.0000
X:49242994:T:G	donor_loss	1.0000
X:49243282:A:AG	acceptor_gain	1.0000
X:49243283:G:GG	acceptor_gain	1.0000
X:49246907:G:GT	donor_gain	1.0000
X:49247637:T:TA	acceptor_gain	1.0000

AlphaMissense

4014 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:49249228:G:C	R534P	0.999
X:49249542:T:G	Y557D	0.999
X:49249552:T:C	L560P	0.999
X:49249664:T:C	L570P	0.999
X:49249715:T:C	L587P	0.999
X:49237228:T:C	F65L	0.998
X:49237230:C:A	F65L	0.998
X:49237230:C:G	F65L	0.998
X:49249189:T:C	L521P	0.998
X:49249233:T:C	F536L	0.998
X:49249235:T:A	F536L	0.998
X:49249235:T:G	F536L	0.998
X:49249257:T:C	F544L	0.998
X:49249259:C:A	F544L	0.998
X:49249259:C:G	F544L	0.998
X:49249513:C:A	A547D	0.998
X:49249555:C:A	A561D	0.998
X:49249561:T:C	L563P	0.998
X:49235656:T:C	I7T	0.997
X:49237229:T:C	F65S	0.997
X:49242053:T:C	F89S	0.997
X:49248875:T:C	I497T	0.997
X:49249222:T:C	L532P	0.997
X:49249252:T:C	L542P	0.997
X:49249547:G:C	K558N	0.997
X:49249547:G:T	K558N	0.997
X:49249709:G:C	R585P	0.997
X:49248872:G:C	R496P	0.996
X:49249210:T:C	L528P	0.996
X:49249542:T:C	Y557H	0.996

dbSNP variants (sampled 300 via entrez): RS1000442115 (X:49235379 T>A,C), RS1000749246 (X:49237658 T>G), RS1000823474 (X:49237076 C>G), RS1002425481 (X:49240133 G>T), RS1002497554 (X:49239566 T>C), RS1002757779 (X:49242367 G>A), RS1004045637 (X:49249362 G>A), RS1004727260 (X:49234382 C>A), RS1004763936 (X:49245851 T>C), RS1004837571 (X:49245354 T>G), RS1006300610 (X:49238896 C>T), RS1006632591 (X:49241257 G>A), RS1006663458 (X:49240636 T>C), RS1007227022 (X:49248875 T>C,G), RS1008245342 (X:49233540 G>A)

Disease associations

OMIM: gene MIM:300859 | disease phenotypes: MIM:300963, MIM:607086, MIM:220210, MIM:304790

GenCC curated gene-disease

Disease	Classification	Inheritance
Ritscher-Schinzel syndrome 2	Strong	X-linked
Ritscher-Schinzel syndrome	Supportive	Autosomal recessive
epilepsy	Limited	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Ritscher-Schinzel syndrome 2	Moderate	XL

Mondo (8): Ritscher-Schinzel syndrome 2 (MONDO:0010499), intellectual disability (MONDO:0001071), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), Ritscher-Schinzel syndrome 1 (MONDO:0009073), obesity disorder (MONDO:0011122), immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (MONDO:0010580), epilepsy (MONDO:0005027), Ritscher-Schinzel syndrome (MONDO:0019078)

Orphanet (6): 3C syndrome (Orphanet:7), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (Orphanet:37042), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

90 total (30 of 90 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000235	Abnormal cranial suture/fontanelle morphology
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000269	Prominent occiput
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000329	Facial hemangioma
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000470	Short neck
HP:0000475	Broad neck
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000567	Chorioretinal coloboma
HP:0000582	Upslanted palpebral fissure
HP:0000612	Iris coloboma
HP:0000648	Optic atrophy
HP:0000835	Adrenal hypoplasia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004785_40	Vitiligo	1.000000e-09

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C535313	3C syndrome (supp.)
C580192	Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066516 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2294021	CCDC22		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.48	Kd	330.9	nM	CHEMBL5653589
6.22	ED50	598.1	nM	CHEMBL5653589
5.90	Kd	1246	nM	CHEMBL3752910
5.65	ED50	2253	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148008: Binding affinity to human CCDC22 incubated for 45 mins by Kinobead based pull down assay	kd	0.3309	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148008: Binding affinity to human CCDC22 incubated for 45 mins by Kinobead based pull down assay	kd	1.2464	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	5
ginger extract	decreases expression, decreases reaction, increases abundance	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	decreases expression, decreases reaction, increases abundance	1
lead acetate	increases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Benzophenoneidum	increases expression	1
Diazinon	increases methylation	1
Ivermectin	decreases expression	1
Oils, Volatile	decreases expression, decreases reaction, increases abundance	1
Ozone	increases abundance, affects expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Acrylamide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651050	Binding	Binding affinity to human CCDC22 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

499 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy