CC2D1A

Summary

CC2D1A (coiled-coil and C2 domain containing 1A, HGNC:30237) is a protein-coding gene on chromosome 19p13.12, encoding Coiled-coil and C2 domain-containing protein 1A (Q6P1N0). Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells.

This gene encodes a transcriptional repressor that binds to a conserved 14-bp 5’-repressor element and regulates expression of the 5-hydroxytryptamine (serotonin) receptor 1A gene in neuronal cells. The DNA binding and transcriptional repressor activities of the protein are inhibited by calcium. A mutation in this gene results in a nonsyndromic form of cognitive disability (MRT3).

Source: NCBI Gene 54862 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 744 total — 30 pathogenic, 33 likely-pathogenic
• Phenotypes (HPO): 10
• MANE Select transcript: NM_017721

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30237
Approved symbol	CC2D1A
Name	coiled-coil and C2 domain containing 1A
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20241, MRT3, Freud-1, Lgd2, TAPE, Aki-1
Ensembl gene	ENSG00000132024
Ensembl biotype	protein_coding
OMIM	610055
Entrez	54862

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 29 protein_coding, 10 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000318003, ENST00000585896, ENST00000586955, ENST00000587508, ENST00000588932, ENST00000589138, ENST00000589224, ENST00000589606, ENST00000589679, ENST00000679637, ENST00000679937, ENST00000680439, ENST00000680895, ENST00000680977, ENST00000681428, ENST00000681846, ENST00000870924, ENST00000870925, ENST00000870926, ENST00000870927, ENST00000870928, ENST00000870929, ENST00000870930, ENST00000870931, ENST00000870932, ENST00000870933, ENST00000870934, ENST00000870935, ENST00000870936, ENST00000870937, ENST00000870938, ENST00000870939, ENST00000870940, ENST00000870941, ENST00000870942, ENST00000933110, ENST00000952979, ENST00000952980, ENST00000952981, ENST00000952982, ENST00000952983

RefSeq mRNA: 2 — MANE Select: NM_017721 NM_001411138, NM_017721

CCDS: CCDS42512, CCDS92537

Canonical transcript exons

ENST00000318003 — 29 exons

Exon	Start	End
ENSE00001780634	13912323	13912438
ENSE00001783446	13912528	13912593
ENSE00002747107	13906201	13906501
ENSE00003465212	13930242	13930289
ENSE00003470742	13926667	13926725
ENSE00003471170	13929534	13929660
ENSE00003482749	13923695	13923811
ENSE00003483892	13926978	13927077
ENSE00003486219	13918746	13918817
ENSE00003502518	13927175	13927265
ENSE00003509077	13926821	13926872
ENSE00003510057	13928124	13928188
ENSE00003515041	13918504	13918576
ENSE00003520778	13918912	13919042
ENSE00003525304	13926517	13926590
ENSE00003526654	13920557	13920668
ENSE00003527532	13913168	13913302
ENSE00003540473	13909823	13909958
ENSE00003559125	13930375	13930879
ENSE00003590502	13923333	13923455
ENSE00003591962	13918070	13918194
ENSE00003625332	13919130	13919202
ENSE00003630044	13919818	13919951
ENSE00003640584	13929379	13929442
ENSE00003663129	13913404	13913638
ENSE00003665778	13923548	13923606
ENSE00003685554	13920750	13920922
ENSE00003688786	13927893	13928030
ENSE00003692862	13930078	13930154

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.2782 / max 163.6229, expressed in 1799 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174197	10.3500	1787
174198	5.3379	1652
174199	0.5903	320

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.13	gold quality
mucosa of transverse colon	UBERON:0004991	97.07	gold quality
cerebellar hemisphere	UBERON:0002245	97.06	gold quality
cerebellar cortex	UBERON:0002129	97.03	gold quality
cerebellum	UBERON:0002037	96.99	gold quality
right frontal lobe	UBERON:0002810	95.89	gold quality
pituitary gland	UBERON:0000007	95.46	gold quality
hypothalamus	UBERON:0001898	95.33	gold quality
right uterine tube	UBERON:0001302	95.31	gold quality
lower esophagus mucosa	UBERON:0035834	95.18	gold quality
primary visual cortex	UBERON:0002436	95.04	gold quality
transverse colon	UBERON:0001157	94.94	gold quality
adenohypophysis	UBERON:0002196	94.91	gold quality
duodenum	UBERON:0002114	94.86	gold quality
anterior cingulate cortex	UBERON:0009835	94.85	gold quality
skin of leg	UBERON:0001511	94.56	gold quality
sural nerve	UBERON:0015488	94.51	gold quality
Ammon’s horn	UBERON:0001954	94.42	gold quality
amygdala	UBERON:0001876	94.39	gold quality
temporal lobe	UBERON:0001871	94.38	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.33	gold quality
zone of skin	UBERON:0000014	94.22	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.15	gold quality
brain	UBERON:0000955	94.00	gold quality
substantia nigra	UBERON:0002038	93.98	gold quality
superior frontal gyrus	UBERON:0002661	93.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.92	gold quality
skin of abdomen	UBERON:0001416	93.90	gold quality
apex of heart	UBERON:0002098	93.70	gold quality
tibial nerve	UBERON:0001323	93.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.51

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
HTR1A	Repression

miRNA regulators (miRDB)

71 targeting CC2D1A, 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-9-5P	100.00	72.28	2361
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-636	99.80	69.58	1500

Literature-anchored findings (GeneRIF, showing 31)

• Freud-1 mediates HDAC-independent repression of the 5-HT1A receptor promoter in neuronal 5-HT1A-positive cells. (PMID:14756806)
• Review of Freud-1 as a repressor of serotonin 1A receptor gene. (PMID:15534042)
• A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive mental retardation. (PMID:16033914)
• Paper describes a function of Cc2d1a/Cc2d1b and their Drosophila homologue l(2)gd in D.melanogaster in Notch trafficking. (PMID:17084358)
• a deletion in the CC2D1A gene has been linked to nonsyndromic mental retardation. This deletion results in the truncation of the helix-loop-helix DNA binding and the C2 domains. (PMID:17394259)
• Freud-1 has a key role in regulating DRD2 expression (PMID:17535813)
• disruption of transcriptional regulation by mutation of Freud-1 may play a role in abnormal brain function leading to mental retardation (PMID:17714190)
• CC2D1A associated with epidermal growth factor receptor (EGFR) in response to EGF stimulation, and was required for Akt activation induced by EGF, but not by insulin-like growth factor 1 (IGF-1). (PMID:18662999)
• Results suggest that Freud-1/Aki1 is a novel receptor-selective scaffold protein for the PDK1/Akt pathway and present a new activation mechanism of Akt. (PMID:18662999)
• Aki1 (Akt kinase-interacting protein 1)/CC2D1A/Freud-1 localized in centrosomes in addition to cytosol and in nucleus. Aki1 interacts with cohesin to prevent premature separase-mediated centriole disengagement. (PMID:19948489)
• Centrosome-associated Aki1 and cohesin play pivotal roles in preventing premature cleavage in centriole cohesion. (PMID:19948489)
• these results indicate that cyclin B1-Cdk1 is a kinase of Aki1 during mitosis and that its phosphorylation of Aki1 may regulate mitotic function. (PMID:20171170)
• Reductions in Freud-1 expression in prefrontal cortex may be associated with early onset of major depressive disorder. (PMID:20392296)
• CC2D1A activates NF-kappaB through the canonical IKK pathway (PMID:20529849)
• central role for TAPE (CC2D1A/Freud-1/Aki-1)in linking TLR3 and TLR4 to innate immune defenses at an early step (PMID:21189260)
• Data suggest that the anti-tumor activity of NF-kappaB inhibitors is associated with p53-mediated activation of autophagy. (PMID:21274377)
• Results suggest the involvement of CC2D1A and CC2D2A in mental retardation in the Han Chinese population, and some specific haplotypes may be susceptible or protective. (PMID:22023432)
• CC2D1A interaction with CHMP4B/4A blocks HIV-1 budding. (PMID:22258254)
• Non-genomic downregulation of 5-HT1A receptor by 17betaestradiol does not involve NUDR and Freud-1 proteins. (PMID:22328058)
• CHMP4B interacts directly with CC2D1A and CC2D1B with nanomolar affinity by forming a 1:1 complex. (PMID:22406677)
• TBK1-associated protein in endolysosomes (TAPE)/CC2D1A is a key regulator linking RIG-I-like receptors to antiviral immunity (PMID:22833682)
• All of the pancreatic cancer cell lines expressed Aki1. Silencing of Aki1 in Panc1 cells reduced the phosphorylation of Akt and increased the phosphorylation of cleaved PARP. (PMID:25036909)
• Null mutations in CC2D1A consistently cause a variable spectrum of presentations including ID, ASD, and seizures. CC2D1A regulates NF-kappaB signaling. (PMID:25066123)
• Aki1 was expressed in human diffuse malignant mesothelioma specimens. Expression correlated with phosphorylated CREB1. Aki1 regulates CREB by modulating protein kinase A activity. The Aki1-CREB axis plays an important role in DMM pathogenesis. (PMID:26294214)
• Both expressions of CC2D1A and HTR1A genes studied on autism spectrum disorder cases and controls were significantly different (PMID:26782176)
• CC2D1A binds to CHMP4B polymers formed on endosomes to regulate the endosomal sorting pathway.CC2D1A regulates degradation and signaling of EGFR and TLR4. (PMID:27769858)
• Unravelling of Hidden Secrets: The Tumour Suppressor Lethal (2) Giant Discs (Lgd)/CC2D1, Notch Signalling and Cancer. (PMID:33034024)
• Monoallelic Mutations in CC2D1A Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction. (PMID:33196317)
• Novel alterations of CC2D1A as a candidate gene in a Turkish sample of patients with autism spectrum disorder. (PMID:33287601)
• Effects of the Cc2d1a/Freud-1 Knockdown in the Hippocampus of BTBR Mice on the Autistic-Like Behavior, Expression of Serotonin 5-HT1A and D2 Dopamine Receptors, and CREB and NF-kB Intracellular Signaling. (PMID:36273889)
• CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow. (PMID:39168639)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	CC2D1A	ENSDARG00000036281
mus_musculus	Cc2d1a	ENSMUSG00000036686
rattus_norvegicus	Cc2d1a	ENSRNOG00000006747
drosophila_melanogaster	l(2)gd1	FBGN0261983
caenorhabditis_elegans	ccct-1	WBGENE00012578

Paralogs (1): CC2D1B (ENSG00000154222)

Protein

Protein identifiers

Coiled-coil and C2 domain-containing protein 1A — Q6P1N0 (reviewed: Q6P1N0)

Alternative names: Akt kinase-interacting protein 1, Five prime repressor element under dual repression-binding protein 1, Putative NF-kappa-B-activating protein 023N

All UniProt accessions (4): Q6P1N0, A0A7P0Z4M5, K7EJY5, K7EMP1

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells. The combination of calcium and ATP specifically inactivates the binding with FRE. May play a role in the altered regulation of HTR1A associated with anxiety and major depression. Mediates HDAC-independent repression of HTR1A promoter in neuronal cell. Performs essential function in controlling functional maturation of synapses. Plays distinct roles depending on its localization. When cytoplasmic, acts as a scaffold protein in the PI3K/PDK1/AKT pathway. Repressor of HTR1A when nuclear. In the centrosome, regulates spindle pole localization of the cohesin subunit SCC1/RAD21, thereby mediating centriole cohesion during mitosis.

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

Post-translational modifications. Phosphorylation on Ser-208 by CDK1 promotes spindle pole localization and association with SCC1/RAD21.

Disease relevance. Intellectual developmental disorder, autosomal recessive 3 (MRT3) [MIM:608443] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C2 domain is required for the repression.

Similarity. Belongs to the CC2D1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6P1N0-1	1	yes
Q6P1N0-2	2

RefSeq proteins (2): NP_001398067, NP_060191* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR006608	CC2D1A/B_DM14	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037772	C2_Freud	Domain
IPR039725	CC2D1A/B	Family

Pfam: PF00168, PF21528

UniProt features (29 total): modified residue 7, region of interest 5, sequence conflict 5, compositionally biased region 4, sequence variant 3, coiled-coil region 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P1N0-F1	74.71	0.42

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 (7): 92, 204, 206, 208, 253, 324, 455

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 169 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_ENDOSOME_ORGANIZATION, GOBP_SYNAPSE_ASSEMBLY, GOBP_VESICLE_ORGANIZATION, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_DENDRITE_MORPHOGENESIS

GO Biological Process (13): regulation of respiratory gaseous exchange by nervous system process (GO:0002087), regulation of transcription by RNA polymerase II (GO:0006357), endosome organization (GO:0007032), learning or memory (GO:0007611), social behavior (GO:0035176), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), long-term synaptic potentiation (GO:0060291), apical dendrite arborization (GO:0150023), regulation of postsynapse assembly (GO:0150052), negative regulation of snRNA transcription by RNA polymerase II (GO:1905381), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of respiratory gaseous exchange (GO:0043576), dendrite arborization (GO:0140059)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), cadherin binding (GO:0045296), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (13): fibrillar center (GO:0001650), nucleus (GO:0005634), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), ciliary basal body (GO:0036064), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
respiratory gaseous exchange by respiratory system	2
transcription by RNA polymerase II	2
behavior	2
negative regulation of transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
microtubule organizing center	2
regulation of respiratory system process	1
nervous system process	1
regulation of DNA-templated transcription	1
endomembrane system organization	1
vesicle organization	1
cognition	1
biological process involved in intraspecies interaction between organisms	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
dendrite arborization	1
apical dendrite morphogenesis	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
snRNA transcription by RNA polymerase II	1
regulation of snRNA transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
regulation of multicellular organismal process	1
dendrite morphogenesis	1
neuron projection arborization	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
cell adhesion molecule binding	1
nucleic acid binding	1
binding	1
nucleolus	1

Protein interactions and networks

STRING

830 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CC2D1A	PRSS12	P56730	909
CC2D1A	CHMP4C	Q96CF2	891
CC2D1A	CHMP4A	Q9BY43	833
CC2D1A	CHMP6	Q96FZ7	817
CC2D1A	CRBN	Q96SW2	802
CC2D1A	VPS4A	Q9UN37	744
CC2D1A	VPS4B	O75351	713
CC2D1A	CHMP5	Q9NZZ3	704
CC2D1A	CHMP1A	Q9HD42	693
CC2D1A	VPS25	Q9BRG1	669
CC2D1A	CHMP3	Q9Y3E7	668
CC2D1A	A0A140T963	A0A140T963	668
CC2D1A	CHMP2A	O43633	651
CC2D1A	DEAF1	O75398	622
CC2D1A	KCNH3	Q9ULD8	617

IntAct

101 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CC2D1A	CHMP4B	psi-mi:“MI:0915”(physical association)	0.660
CEP170	KIF2A	psi-mi:“MI:2364”(proximity)	0.650
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
TSPAN3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
CRYAB	CCDC85C	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
Dlg4	CC2D1A	psi-mi:“MI:0407”(direct interaction)	0.440
CEP162	CCP110	psi-mi:“MI:2364”(proximity)	0.420
CC2D1A	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
CC2D1A	CHMP4A	psi-mi:“MI:0915”(physical association)	0.370
CC2D1A	CHMP4C	psi-mi:“MI:0915”(physical association)	0.370
CDC37	CC2D1A	psi-mi:“MI:0915”(physical association)	0.370
Chmp4b		psi-mi:“MI:0914”(association)	0.350
Immt	GOSR1	psi-mi:“MI:0914”(association)	0.350
Chmp4b	BDP1	psi-mi:“MI:0914”(association)	0.350
CHMP4B		psi-mi:“MI:0914”(association)	0.350
CHMP4B	ELOC	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CHMP4B	CC2D1B	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350

BioGRID (196): CC2D1A (Affinity Capture-MS), CC2D1A (Affinity Capture-MS), LRWD1 (Co-fractionation), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS), CC2D1A (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JV04, B0V207, D3Z8X7, D3ZFJ3, D3ZND0, F1LM81, G9CGD6, O00499, O08539, O08839, O12940, O60308, O60784, O75674, O88746, P42567, P55194, Q05DH4, Q0GNC1, Q0IHV1, Q27J81, Q3B7M3, Q3UN70, Q4KLN4, Q505K2, Q5FVK6, Q5T0F9, Q5U3K5, Q66HA5, Q68EF0, Q6P1N0, Q6P5E6, Q6P9Q4, Q6P9Q6, Q80V31, Q80V94, Q8BMI3, Q8BRN9, Q8K1A6, Q8R0H9

Diamond homologs: Q29M42, Q5FVK6, Q5T0F9, Q66HA5, Q6P1N0, Q6PF54, Q8BRN9, Q8K1A6, Q9U2M8, Q9VKJ9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CC2D1A	“down-regulates quantity by repression”	HTR1A	“transcriptional regulation”
CC2D1A	“up-regulates activity”	RAD21	binding
CyclinB/CDK1	“up-regulates activity”	CC2D1A	phosphorylation
CDK1	“up-regulates activity”	CC2D1A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 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
Anchoring of the basal body to the plasma membrane	13	17.9×	1e-10
Loss of Nlp from mitotic centrosomes	9	17.4×	3e-07
Loss of proteins required for interphase microtubule organization from the centrosome	9	17.4×	3e-07
AURKA Activation by TPX2	9	16.7×	3e-07
Regulation of PLK1 Activity at G2/M Transition	10	15.5×	2e-07
Recruitment of mitotic centrosome proteins and complexes	9	14.9×	8e-07
Recruitment of NuMA to mitotic centrosomes	9	12.8×	3e-06
Signaling by Nuclear Receptors	6	7.5×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	6	19.1×	3e-04
macroautophagy	5	10.9×	6e-03
cilium assembly	10	6.7×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	33
Uncertain significance	221
Likely benign	357
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1322031	NM_017721.5(CC2D1A):c.1764+1G>C	Pathogenic
1699097	NM_017721.5(CC2D1A):c.2347C>T (p.Arg783Ter)	Pathogenic
228325	NM_017721.5(CC2D1A):c.748+1G>T	Pathogenic
2703274	NM_017721.5(CC2D1A):c.1969del (p.Met657fs)	Pathogenic
2705325	NM_017721.5(CC2D1A):c.2511_2512del (p.Gly838fs)	Pathogenic
2705339	NM_017721.5(CC2D1A):c.1882_1891del (p.Val628fs)	Pathogenic
2706440	NM_017721.5(CC2D1A):c.2137C>T (p.Gln713Ter)	Pathogenic
2719486	NC_000019.10:g.13927896_13927905del	Pathogenic
2736827	NM_017721.5(CC2D1A):c.347del (p.Lys116fs)	Pathogenic
2743479	NM_017721.5(CC2D1A):c.1711G>T (p.Glu571Ter)	Pathogenic
2747167	NM_017721.5(CC2D1A):c.163C>T (p.Gln55Ter)	Pathogenic
2749373	NM_017721.5(CC2D1A):c.1048G>T (p.Glu350Ter)	Pathogenic
2750805	NM_017721.5(CC2D1A):c.1813del (p.Glu605fs)	Pathogenic
2752522	NM_017721.5(CC2D1A):c.938dup (p.Pro314fs)	Pathogenic
2763099	NM_017721.5(CC2D1A):c.982C>T (p.Gln328Ter)	Pathogenic
2772300	NM_017721.5(CC2D1A):c.362dup (p.Pro122fs)	Pathogenic
2817527	NM_017721.5(CC2D1A):c.1168C>T (p.Arg390Ter)	Pathogenic
2820954	NM_017721.5(CC2D1A):c.1807dup (p.Ile603fs)	Pathogenic
2832444	NM_017721.5(CC2D1A):c.810_813dup (p.Leu272fs)	Pathogenic
2835658	NM_017721.5(CC2D1A):c.1449_1489del41 (p.Lys484fs)	Pathogenic
2836963	NM_017721.5(CC2D1A):c.938del (p.Pro313fs)	Pathogenic
2842001	NM_017721.5(CC2D1A):c.1015dup (p.Thr339fs)	Pathogenic
2845607	NM_017721.5(CC2D1A):c.707del (p.Pro236fs)	Pathogenic
2854618	NM_017721.5(CC2D1A):c.1212del (p.Val405fs)	Pathogenic
2856036	NM_017721.5(CC2D1A):c.316dup (p.Glu106fs)	Pathogenic
3242704	NC_000019.9:g.(?14017255)(14041208_?)del	Pathogenic
3242705	NC_000019.9:g.(?14034126)(14034644_?)del	Pathogenic
3242706	NC_000019.9:g.(?14028863)(14031755_?)del	Pathogenic
4735437	NM_017721.5(CC2D1A):c.621C>G (p.Tyr207Ter)	Pathogenic
4755702	NM_017721.5(CC2D1A):c.2012del (p.Pro671fs)	Pathogenic

SpliceAI

3521 predictions. Top by Δscore:

Variant	Effect	Δscore
19:13909819:CTAGC:C	acceptor_loss	1.0000
19:13909820:TA:T	acceptor_loss	1.0000
19:13909821:A:AG	acceptor_gain	1.0000
19:13909821:AGCT:A	acceptor_gain	1.0000
19:13909821:AGCTG:A	acceptor_gain	1.0000
19:13909822:G:GT	acceptor_gain	1.0000
19:13909822:GC:G	acceptor_gain	1.0000
19:13909822:GCT:G	acceptor_gain	1.0000
19:13909822:GCTG:G	acceptor_gain	1.0000
19:13909822:GCTGG:G	acceptor_gain	1.0000
19:13909898:GC:G	donor_gain	1.0000
19:13909959:G:GA	donor_loss	1.0000
19:13912317:C:A	acceptor_gain	1.0000
19:13912320:CAG:C	acceptor_loss	1.0000
19:13912321:A:G	acceptor_loss	1.0000
19:13912434:TGCTG:T	donor_gain	1.0000
19:13912435:GCTG:G	donor_gain	1.0000
19:13912435:GCTGG:G	donor_gain	1.0000
19:13912436:CTGG:C	donor_loss	1.0000
19:13912437:TGGTG:T	donor_loss	1.0000
19:13912439:G:GG	donor_gain	1.0000
19:13912439:GT:G	donor_loss	1.0000
19:13912440:T:G	donor_loss	1.0000
19:13913163:CACA:C	acceptor_loss	1.0000
19:13913164:ACAGC:A	acceptor_loss	1.0000
19:13913165:CA:C	acceptor_loss	1.0000
19:13913166:A:AC	acceptor_loss	1.0000
19:13913166:A:AG	acceptor_gain	1.0000
19:13913166:AGCC:A	acceptor_gain	1.0000
19:13913167:G:GC	acceptor_gain	1.0000

AlphaMissense

6121 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:13930270:G:C	R939P	0.999
19:13920812:G:C	A511P	0.998
19:13920852:T:C	L524P	0.998
19:13920860:G:C	A527P	0.998
19:13926697:T:A	V682D	0.998
19:13929398:A:C	S847R	0.998
19:13929400:C:A	S847R	0.998
19:13929400:C:G	S847R	0.998
19:13920779:C:A	R500S	0.997
19:13920780:G:C	R500P	0.997
19:13920792:T:C	L504P	0.997
19:13920804:C:A	A508E	0.997
19:13920817:G:C	K512N	0.997
19:13920817:G:T	K512N	0.997
19:13920840:C:A	A520D	0.997
19:13927927:T:C	L784P	0.997
19:13930276:T:C	L941P	0.997
19:13920800:G:C	A507P	0.996
19:13920803:G:C	A508P	0.996
19:13927992:T:A	W806R	0.996
19:13927992:T:C	W806R	0.996
19:13930126:C:A	A920D	0.996
19:13920870:T:C	L530P	0.995
19:13927204:G:A	G752E	0.995
19:13930093:T:C	L909P	0.995
19:13930253:G:C	K933N	0.995
19:13930253:G:T	K933N	0.995
19:13930257:G:C	A935P	0.995
19:13919032:G:C	R380P	0.994
19:13919133:T:G	Y385D	0.994

dbSNP variants (sampled 300 via entrez): RS1000035776 (19:13931315 C>T), RS1000262728 (19:13914315 C>T), RS1000348913 (19:13927429 AC>A), RS1000407835 (19:13920200 A>G), RS1000456755 (19:13909357 C>G,T), RS1000634326 (19:13914740 A>G), RS1000919214 (19:13904552 C>T), RS1001045977 (19:13910204 C>T), RS1001058022 (19:13910432 A>G,T), RS1001176176 (19:13926038 A>G), RS1001210313 (19:13929712 T>G), RS1001375259 (19:13908148 G>T), RS1001435114 (19:13904279 C>G), RS1001445501 (19:13909869 A>C), RS1001590296 (19:13919458 G>C)

Disease associations

OMIM: gene MIM:610055 | disease phenotypes: MIM:608443, MIM:249500, MIM:209850, MIM:619245

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 3	Definitive	Autosomal recessive
complex neurodevelopmental disorder	Definitive	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AR

Mondo (8): intellectual disability, autosomal recessive 3 (MONDO:0012037), autosomal recessive non-syndromic intellectual disability (MONDO:0019502), intellectual disability (MONDO:0001071), autism (MONDO:0005260), premature ovarian failure 19 (MONDO:0030985), ciliopathy (MONDO:0005308), cerebral palsy (MONDO:0006497), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (3): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Ciliopathy (Orphanet:363250), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

10 total (12 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000253	Progressive microcephaly
HP:0000338	Hypomimic face
HP:0000736	Short attention span
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001263	Global developmental delay
HP:0002546	Incomprehensible speech
HP:0010864	Severe intellectual disability
HP:0011463	Childhood onset
HP:0000717	Autism
HP:0100021	Cerebral palsy

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002547	Cerebral Palsy	C10.228.140.140.254
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C563929	Mental Retardation, Autosomal Recessive 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
2-palmitoylglycerol	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1