CIC

Summary

CIC (capicua transcriptional repressor, HGNC:14214) is a protein-coding gene on chromosome 19q13.2, encoding Protein capicua homolog (Q96RK0). Transcriptional repressor which plays a role in development of the central nervous system (CNS). It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is an ortholog of the Drosophila melanogaster capicua gene, and is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors. This protein contains a conserved HMG domain that is involved in DNA binding and nuclear localization, and a conserved C-terminus. Studies suggest that the N-terminal region of this protein interacts with Atxn1 (GeneID:6310), to form a transcription repressor complex, and in vitro studies suggest that polyglutamine-expansion of ATXN1 may alter the repressor activity of this complex. Mutations in this gene have been associated with olidogdendrogliomas (PMID:21817013). In addition, translocation events resulting in gene fusions of this gene with both DUX4 (GeneID:100288687) and FOXO4 (GeneID:4303) have been associated with round cell sarcomas. There are multiple pseudogenes of this gene found on chromosomes 1, 4, 6, 7, 16, 20, and the Y chromosome. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 23152 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 970 total — 32 pathogenic, 48 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001386298

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14214
Approved symbol	CIC
Name	capicua transcriptional repressor
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0306
Ensembl gene	ENSG00000079432
Ensembl biotype	protein_coding
OMIM	612082
Entrez	23152

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000160740, ENST00000571033, ENST00000572681, ENST00000573349, ENST00000575287, ENST00000575354, ENST00000575839, ENST00000576505, ENST00000681038, ENST00000684265, ENST00000868566, ENST00000940332, ENST00000940333

RefSeq mRNA: 7 — MANE Select: NM_001386298 NM_001304815, NM_001379480, NM_001379482, NM_001379484, NM_001379485, NM_001386298, NM_015125

CCDS: CCDS12601, CCDS92632

Canonical transcript exons

ENST00000681038 — 21 exons

Exon	Start	End
ENSE00000358709	42288888	42289090
ENSE00000358713	42291558	42291745
ENSE00000709351	42294604	42294735
ENSE00000709355	42294173	42294304
ENSE00000709359	42293935	42294089
ENSE00000709362	42293592	42293836
ENSE00000709365	42292956	42293281
ENSE00000709368	42292566	42292859
ENSE00000709371	42292300	42292466
ENSE00000709411	42292086	42292207
ENSE00000709413	42290233	42291466
ENSE00000709415	42289848	42289951
ENSE00000709421	42289181	42289406
ENSE00000709423	42287810	42287975
ENSE00000709425	42287545	42287727
ENSE00000709426	42287320	42287449
ENSE00000952288	42286771	42286920
ENSE00000952289	42287006	42287240
ENSE00002660234	42269252	42269381
ENSE00002667675	42271774	42274577
ENSE00002670469	42294824	42295796

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 97.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9172 / max 196.3813, expressed in 1798 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176130	4.7433	1576
176138	3.4856	1358
176132	2.6780	1431
176140	1.1285	707
176137	1.0518	631
176139	0.9763	586
176133	0.7897	483
176131	0.0641	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.80	gold quality
cerebellar hemisphere	UBERON:0002245	97.49	gold quality
cerebellar cortex	UBERON:0002129	97.48	gold quality
olfactory bulb	UBERON:0002264	96.93	silver quality
sural nerve	UBERON:0015488	96.84	gold quality
cerebellum	UBERON:0002037	96.74	gold quality
type B pancreatic cell	CL:0000169	96.12	silver quality
right testis	UBERON:0004534	96.12	gold quality
mucosa of stomach	UBERON:0001199	96.07	gold quality
left testis	UBERON:0004533	96.02	gold quality
right ovary	UBERON:0002118	95.95	gold quality
body of uterus	UBERON:0009853	95.83	gold quality
adenohypophysis	UBERON:0002196	95.76	gold quality
ventricular zone	UBERON:0003053	95.73	gold quality
paraflocculus	UBERON:0005351	95.72	gold quality
cortical plate	UBERON:0005343	95.67	gold quality
left ovary	UBERON:0002119	95.33	gold quality
left uterine tube	UBERON:0001303	95.23	gold quality
ganglionic eminence	UBERON:0004023	95.04	gold quality
right frontal lobe	UBERON:0002810	95.03	gold quality
pituitary gland	UBERON:0000007	94.95	gold quality
cerebellar vermis	UBERON:0004720	94.95	gold quality
peripheral nervous system	UBERON:0000010	94.65	gold quality
tibial nerve	UBERON:0001323	94.65	gold quality
endocervix	UBERON:0000458	94.62	gold quality
apex of heart	UBERON:0002098	94.43	gold quality
ectocervix	UBERON:0012249	94.43	gold quality
popliteal artery	UBERON:0002250	94.36	gold quality
tibial artery	UBERON:0007610	94.35	gold quality
amygdala	UBERON:0001876	94.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CCNE1	Repression
ETV5	Activation
RASA1

Upstream regulators (CollecTRI, top): NCOR2, PPARA, PPARG, SP1, SREBF1

miRNA regulators (miRDB)

85 targeting CIC, 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-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Results describe the identification and characterization of a new gene, Cic, in both human and mouse genomes, that is implicated in granule cell development. (PMID:12393275)
• Medulloblastomas exhibited the highest level of CIC expression, although the level of expression varied between different medulloblastoma subtypes. Expression was most common in tumors of the CNS in general. (PMID:15981098)
• fusion transcripts involving CIC (19q13) and DUX4 (4q35) were confirmed to be present in both primitive round cell sarcomas, further defining the breakpoints seen by genomic analysis. (PMID:19837261)
• human capicua represses mRNA expression for PEA3 (polyoma enhancer activator 3) Ets transcription factors ETV1, ETV4 and ETV5 (PMID:21087211)
• CIC gene was mutated in 6 oligodendrogliomas and FUBP1 gene was mutated in 2; 27 additional oligodendrogliomas showed 12 and 3 more tumors with mutations of CIC and FUBP1; results suggest role of these genes in biology and pathology of oligodendrocytes (PMID:21817013)
• Our detailed study of genetic aberrations in oligodendroglioma suggests a functional interaction between CIC mutation, IDH1/2 mutation, and 1p/19q co-deletion (PMID:22072542)
• Found CIC and FUBP1 mutations in oligodendrogliomas and demonstrate the presence of these mutations in oligoastrocytomas. (PMID:22588899)
• Analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). (PMID:22869205)
• CIC-DUX4 sarcoma represents a novel translocation-associated sarcoma with distinctive histopathologic features and rapid disease progression. (PMID:23887164)
• We conclude that absent CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors. (PMID:24030748)
• CIC acts as a tumor suppressor in these tumors, whereas FUBP1 might play only a minor role (PMID:24086756)
• It is a supportive diagnostic marker for oligodendroglial tumors with the 1p/19q co-deletion. (PMID:24197863)
• The distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from Ewing sarcoma. (PMID:24723486)
• Downregulation of CIC protein levels was not associated with ETV1 or pMEK1/2 expression, KIT and PDGFRA mutations, copy number variations (CNV) of 19q13, and clinical factors. (PMID:24897389)
• Case Report: CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. (PMID:25007147)
• Our study showed for the first time a cooperative reduction in clonogenicity in cells co-expressing IDH1-R132H and mutant CIC proteins (PMID:25277207)
• CIC mutations result in protein inactivation and poorer outcome in patients with a 1p19q codeleted glioma. (PMID:26017892)
• miR-93/miR-106b/miR-375-CIC-CRABP1 is a novel key regulatory axis in prostate cancer progression (PMID:26124181)
• With the advent of large-scale genome sequencing technology, molecular genetic alterations in CIC promoter have now been identified in the majority of oligodendrogliomas (PMID:26545048)
• CIC-rearranged sarcomas are distinct from Ewing sarcomas clinically, morphologically, and immunohistochemically, and they should be considered a separate entity rather than being grouped within the same family of tumors. (PMID:26685084)
• Report CIC genetic alterations in angiosarcomas. (PMID:26735859)
• analysis of homozygous deletions of 19q13.2 and CIC in neuroblastoma (PMID:26794043)
• The aim of this study was to describe seven cases of CIC-DUX4 fusion-positive sarcomas, including the first reported example arising primarily in bone. Our series confirms that CIC-DUX4 fusion-positive sarcomas are aggressive tumours with an adverse prognosis (PMID:27079694)
• Targeted next-generation sequencing of CIC-DUX4 soft tissue sarcomas demonstrates low mutational burden and recurrent chromosome 1p loss. (PMID:27664537)
• Capicua underexpression is associated with lung cancer metastasis. (PMID:27869830)
• The ATXN1L-CIC-ETS transcription factor axis as a mediator of resistance to MAPKi. (PMID:28178529)
• Case Report: genetically distinct variant of CIC-rearranged sarcomas with a novel NUTM2A-CIC fusion. (PMID:28188754)
• Data indicate that the HMG-box of Capicua (CIC) does not bind DNA alone but instead requires a distant motif (referred to as C1) present at the C-terminus of all CIC proteins. (PMID:28278156)
• CIC deficiency was associated with disruptions in the expression of genes involved in cell-cell adhesion, and in the development of several cell and tissue types. We also showed that loss of CIC leads to overexpression of downstream members of the mitogen-activated protein kinase (MAPK) signalling cascade, indicating that CIC deficiency may present a novel mechanism for activation of this oncogenic pathway. (PMID:28295365)
• Findings show CIC-DUX4 sarcomas occur mostly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior survival compared with Ewing sarcoma. Results support classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors. (PMID:28346326)
• Case Report: t(10;19) CIC-DUX4 undifferentiated small round cell sarcoma of the abdominal wall. (PMID:28645808)
• Results indicate an important role for transcriptional repression factor Capicua (CIC) in regulating neural cell proliferation and lineage specification, and suggest that CIC mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma. (PMID:28939681)
• Fluorescence in situ hybridization and targeted next-generation sequencing identified a CIC-NUTM1 fusion resulting from t(15;19)(q14;q13.2). In light of morphologic features that overlap with those of NC from typical anatomical sites we have seen previously, the tumor was best classified as falling within the NC spectrum rather than CIC-associated sarcoma. (PMID:29700887)
• Case Reports: primary CIC-rearranged renal sarcomas including 1 case with CIC-NUTM1 fusion. (PMID:29901569)
• This study highlights the CIC-ATXN1-ATXN1L axis as a more potent regulator of the cell cycle than previously appreciated (PMID:30093628)
• CIC is a powerful tumor suppressor affecting the RAS-MAPK pathway in neuroblastoma (PMID:30115695)
• CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population (PMID:30407212)
• these results identify Cic as an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an oligodendrocyte precursor cells -like identity via Ets overactivity. (PMID:31043608)
• Absence of seizure history and subventricular zone involvement (-) was associated with a higher incidence of CIC mutation in CIC-mutant oligodendroglial tumours (PMID:31215432)
• Expanding the differential of superficial tumors with round-cell morphology: Report of three cases of CIC-rearranged sarcoma, a potentially under-recognized entity. (PMID:31886887)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cicb	ENSDARG00000055502
danio_rerio	cica	ENSDARG00000071150
mus_musculus	Cic	ENSMUSG00000005442
rattus_norvegicus	Cic	ENSRNOG00000056118
drosophila_melanogaster	cic	FBGN0262582
caenorhabditis_elegans		WBGENE00001560

Paralogs (1): BBX (ENSG00000114439)

Protein

Protein identifiers

Protein capicua homolog — Q96RK0 (reviewed: Q96RK0)

All UniProt accessions (6): Q96RK0, A0A0A0MQR4, I3L135, I3L1Q4, I3L2J0, I3L373

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor which plays a role in development of the central nervous system (CNS). In concert with ATXN1 and ATXN1L, involved in brain development.

Subunit / interactions. Found in a complex with ATXN1 and ATXN1L. Interacts with ATXN1. Interacts with ATXN1.

Subcellular location. Nucleus.

Tissue specificity. Expressed in fetal brain.

Disease relevance. Intellectual developmental disorder, autosomal dominant 45 (MRD45) [MIM:617600] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD45 patients manifest developmental delay, variable intellectual disability, and behavioral disorders, including autistic features, attention deficit, and hyperactivity. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Expressed in medulloblastoma, a pediatric brain tumor which may arise from the granule cell lineage.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96RK0-1	1	yes
Q96RK0-2	2

RefSeq proteins (7): NP_001291744, NP_001366409, NP_001366411, NP_001366413, NP_001366414, NP_001373227, NP_055940 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR032147	Cic_dom	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR052412	CC-Dev_Transcription_Reg	Family
IPR058606	HTH_Cic_C	Domain
IPR058607	HMG-box_Cic-like	Domain

Pfam: PF00505, PF16090, PF25981

UniProt features (93 total): compositionally biased region 28, modified residue 28, region of interest 18, sequence variant 7, helix 5, strand 3, splice variant 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6KZG	X-RAY DIFFRACTION	2
4J2J	X-RAY DIFFRACTION	2.5
6KZH	X-RAY DIFFRACTION	2.65
7M5W	X-RAY DIFFRACTION	2.95
6JRP	X-RAY DIFFRACTION	3
4J2L	X-RAY DIFFRACTION	3.15
2M41	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RK0-F1	41.12	0.08

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 (28): 776, 780, 1055, 1082, 1099, 1186, 1271, 1340, 1345, 1405, 1609, 1630, 1648, 1772, 1843, 2177, 2200, 2203, 2260, 2282 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 257 (showing top): GOBP_MEMORY, SHEPARD_BMYB_MORPHOLINO_UP, WANG_CLIM2_TARGETS_UP, GOBP_COGNITION, MYOGENIN_Q6, GOBP_BEHAVIOR, PAX4_01, TGCACTT_MIR519C_MIR519B_MIR519A, LFA1_Q6, SHEPARD_CRASH_AND_BURN_MUTANT_UP, AAGCCAT_MIR135A_MIR135B, COUP_01, GOBP_LEARNING, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTRASPECIES_INTERACTION_BETWEEN_ORGANISMS, GOBP_HEAD_DEVELOPMENT

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), brain development (GO:0007420), learning (GO:0007612), memory (GO:0007613), social behavior (GO:0035176), negative regulation of DNA-templated transcription (GO:0045892), lung alveolus development (GO:0048286)

GO Molecular Function (5): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), chromatin binding (GO:0003682), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
DNA-templated transcription	2
learning or memory	2
binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
central nervous system development	1
animal organ development	1
head development	1
behavior	1
biological process involved in intraspecies interaction between organisms	1
negative regulation of RNA biosynthetic process	1
lung development	1
anatomical structure development	1
transcription cis-regulatory region binding	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular_component	1

Protein interactions and networks

STRING

876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CIC	RBM17	Q96I25	847
CIC	ATXN1	P54253	813
CIC	ATXN1L	P0C7T5	808
CIC	ETV5	P41161	566
CIC	EGFR	P00533	565
CIC	UBQLN4	Q9NRR5	553
CIC	PQBP1	O60828	541
CIC	DUX4L2	P0CJ85	540
CIC	PLEKHG4	Q58EX7	535
CIC	NHLH1	Q02575	512
CIC	DNAJB6	O75190	510
CIC	FUBP1	Q96AE4	507
CIC	HSPA13	P48723	496
CIC	UBQLN2	Q9UHD9	491
CIC	ERBB4	Q15303	485

IntAct

109 interactions, top by confidence:

A	B	Type	Score
ATXN1	YWHAH	psi-mi:“MI:0914”(association)	0.840
CIC	ATXN1	psi-mi:“MI:0915”(physical association)	0.820
ATXN1	CIC	psi-mi:“MI:0915”(physical association)	0.820
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
GOLGA2	CIC	psi-mi:“MI:0915”(physical association)	0.660
ZBTB18	HSPA8	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAZ	CIC	psi-mi:“MI:0915”(physical association)	0.540
MAD2L1	PPIP5K2	psi-mi:“MI:0914”(association)	0.530
CIC	CPAP	psi-mi:“MI:0915”(physical association)	0.510
FOS	MYO1C	psi-mi:“MI:2364”(proximity)	0.480
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
EN1	NFIB	psi-mi:“MI:2364”(proximity)	0.470
CIC	RAD50	psi-mi:“MI:0915”(physical association)	0.400
CIC		psi-mi:“MI:0915”(physical association)	0.370
CIC	CSNK2B	psi-mi:“MI:0915”(physical association)	0.370
CIC	PLK1	psi-mi:“MI:0915”(physical association)	0.370
FOXK2	PHF20L1	psi-mi:“MI:0914”(association)	0.350
ATXN1		psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ZBTB18	ZBTB42	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
MAD2L1	MED19	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (735): CIC (Affinity Capture-MS), CIC (Proximity Label-MS), CIC (Affinity Capture-MS), CIC (Affinity Capture-MS), CIC (Affinity Capture-MS), CIC (Proximity Label-MS), CIC (Affinity Capture-MS), CIC (Affinity Capture-MS), CIC (Affinity Capture-MS), CIC (Proximity Label-MS), CIC (Proximity Label-MS), CIC (Affinity Capture-RNA), CIC (Proximity Label-MS), ACLY (Affinity Capture-Western), CIC (Affinity Capture-Western)

ESM2 similar proteins: A0A0U1RRK4, A0A1W2PPE3, A0A1W2PR82, A0A2Z4LIS9, A2VE02, A4D1S0, A5PKC7, A5PL33, A6H7B4, A6NEL2, A6QP24, A6QPM6, A8MTW9, A8MYA2, D3ZAQ5, D4AAA5, E7EW31, O75474, O75638, O89113, O94850, P0C7X2, P14652, P50617, P70339, Q2KIS6, Q3UN58, Q5JPB2, Q5VZ46, Q6GQX2, Q6NZ36, Q6ZSJ8, Q6ZW13, Q76NI1, Q7TNS8, Q80TS7, Q86UU5, Q8IWN7, Q8N6K4, Q8N944

Diamond homologs: A0A0G2JTZ2, A4IIJ8, A4QNG3, A5A763, B0ZTE2, B1H349, B3DLD3, B3DM43, B7ZR65, F1LYL9, F1M8W4, O18896, O42569, O55170, O60248, O60381, O94993, O95416, P35710, P35711, P35712, P35713, P40645, P40647, P40649, P43267, P43680, P48430, P48431, P48432, P48434, P48436, P54231, P56693, P57073, P57074, P61259, P61753, P61754, Q04886

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
MAPK1	down-regulates	CIC	phosphorylation
MAPK3	down-regulates	CIC	phosphorylation
RPS6KA1	down-regulates	CIC	phosphorylation
RPS6KA3	down-regulates	CIC	phosphorylation
ERK1/2	down-regulates	CIC	phosphorylation
RPS6K	down-regulates	CIC	phosphorylation
Gbeta	down-regulates	CIC	phosphorylation
CIC	“up-regulates activity”	Sin3B_complex	binding
CIC	“up-regulates activity”	“SWI/SNF complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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
Activation of BAD and translocation to mitochondria	6	59.3×	7e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	52.4×	9e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	52.4×	9e-08
Activation of BH3-only proteins	6	38.7×	5e-07
RHO GTPases activate PKNs	6	24.7×	5e-06
Intrinsic Pathway for Apoptosis	6	22.8×	7e-06
Deactivation of the beta-catenin transactivating complex	7	21.2×	1e-06
Transcriptional and post-translational regulation of MITF-M expression and activity	8	18.5×	5e-07

GO biological processes:

GO term	Partners	Fold	FDR
neuron fate specification	5	34.1×	3e-05
protein targeting	5	17.8×	4e-04
cartilage development	7	17.1×	2e-05
positive regulation of miRNA transcription	6	16.9×	1e-04
chondrocyte differentiation	5	14.6×	1e-03
cell fate commitment	5	14.3×	1e-03
retina development in camera-type eye	5	12.4×	1e-03
anatomical structure morphogenesis	9	12.2×	9e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	48
Uncertain significance	507
Likely benign	266
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030471	NM_001386298.1(CIC):c.3400C>T (p.Gln1134Ter)	Pathogenic
1064629	NM_001386298.1(CIC):c.3179+1G>T	Pathogenic
1064660	NC_000019.10:g.42032860_42297536del	Pathogenic
1301398	NM_001386298.1(CIC):c.1100dup (p.Pro368fs)	Pathogenic
1301400	NM_001386298.1(CIC):c.6166_6167del (p.Ala2056fs)	Pathogenic
1708217	NM_001386298.1(CIC):c.3059dup (p.His1021fs)	Pathogenic
1708720	NM_001386298.1(CIC):c.6999del (p.Asn2334fs)	Pathogenic
1805941	NM_001386298.1(CIC):c.6074dup (p.Ser2026fs)	Pathogenic
2233709	NM_001386298.1(CIC):c.3704C>G (p.Ser1235Ter)	Pathogenic
2502532	NM_001386298.1(CIC):c.5421del (p.Ala1809fs)	Pathogenic
3063953	NC_000019.9:g.(?42785739)(42791254_?)del	Pathogenic
3075672	NM_001386298.1(CIC):c.1027del (p.Trp343fs)	Pathogenic
3234056	NM_001386298.1(CIC):c.2322_2323del (p.Arg775fs)	Pathogenic
3375795	NM_001386298.1(CIC):c.6897C>A (p.Tyr2299Ter)	Pathogenic
3772406	NM_001386298.1(CIC):c.6292del (p.Val2098fs)	Pathogenic
3772515	NM_001386298.1(CIC):c.4604del (p.Asn1535fs)	Pathogenic
4002955	NM_001386298.1(CIC):c.6291del (p.Val2098fs)	Pathogenic
422592	NM_001386298.1(CIC):c.5421dup (p.Lys1808fs)	Pathogenic
4228914	NM_001386298.1(CIC):c.3719del (p.Pro1240fs)	Pathogenic
4279548	NM_001386298.1(CIC):c.6367C>T (p.Arg2123Ter)	Pathogenic
431168	NM_001386298.1(CIC):c.3784C>T (p.Arg1262Ter)	Pathogenic
431169	NM_001386298.1(CIC):c.4528_4535dup (p.Glu1513fs)	Pathogenic
431170	NM_001386298.1(CIC):c.5298_5313del (p.Pro1767fs)	Pathogenic
437890	NM_001386298.1(CIC):c.4201C>T (p.Arg1401Trp)	Pathogenic
4526788	NM_001386298.1(CIC):c.4006C>T (p.Gln1336Ter)	Pathogenic
4725206	NM_001386298.1(CIC):c.6103dup (p.Thr2035fs)	Pathogenic
4845401	NM_001386298.1(CIC):c.4169_4170insT (p.Glu1391fs)	Pathogenic
504201	NM_001386298.1(CIC):c.4881dup (p.Gly1628fs)	Pathogenic
521984	NM_001386298.1(CIC):c.7046dup (p.Asp2349fs)	Pathogenic
633530	NM_001386298.1(CIC):c.2795-3881_5255del	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

15872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:42286806:T:C	F35L	1.000
19:42286808:C:A	F35L	1.000
19:42286808:C:G	F35L	1.000
19:42286812:T:A	W37R	1.000
19:42286812:T:C	W37R	1.000
19:42286814:G:C	W37C	1.000
19:42286814:G:T	W37C	1.000
19:42287561:T:A	I200N	1.000
19:42287561:T:G	I200S	1.000
19:42287563:C:G	R201G	1.000
19:42287566:C:G	R202G	1.000
19:42287566:C:T	R202W	1.000
19:42287569:C:A	P203T	1.000
19:42287569:C:T	P203S	1.000
19:42287570:C:A	P203H	1.000
19:42287570:C:G	P203R	1.000
19:42287570:C:T	P203L	1.000
19:42287573:T:A	M204K	1.000
19:42287573:T:C	M204T	1.000
19:42287573:T:G	M204R	1.000
19:42287574:G:A	M204I	1.000
19:42287574:G:C	M204I	1.000
19:42287574:G:T	M204I	1.000
19:42287575:A:C	N205H	1.000
19:42287575:A:G	N205D	1.000
19:42287576:A:T	N205I	1.000
19:42287577:T:A	N205K	1.000
19:42287577:T:G	N205K	1.000
19:42287579:C:A	A206D	1.000
19:42287579:C:T	A206V	1.000

dbSNP variants (sampled 300 via entrez): RS1000002559 (19:42285275 G>A), RS1000033675 (19:42284965 C>G,T), RS1000039086 (19:42270874 C>T), RS1000054634 (19:42268654 G>C), RS1000230551 (19:42278165 A>G), RS1000371728 (19:42281153 T>C,G), RS1000422044 (19:42271348 A>G), RS1000422780 (19:42280859 T>G), RS1000547994 (19:42288668 G>T), RS1000611100 (19:42293700 G>A,T), RS1000642413 (19:42293487 C>T), RS1000646445 (19:42272521 G>A), RS1000755989 (19:42279682 C>T), RS1000916175 (19:42288848 A>G), RS1000999676 (19:42283101 G>A,C)

Disease associations

OMIM: gene MIM:612082 | disease phenotypes: MIM:617600, MIM:617101, MIM:213000, MIM:156200, MIM:607086, MIM:618725, MIM:617268

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 45	Definitive	Autosomal dominant
cerebral folate deficiency	Strong	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (16): intellectual disability, autosomal dominant 45 (MONDO:0030910), syndromic craniosynostosis (MONDO:0015338), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), autism spectrum disorder (MONDO:0005258), Dias-Logan syndrome (MONDO:0014914), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), intellectual disability, autosomal dominant 1 (MONDO:0007974), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), hearing loss disorder (MONDO:0005365), hereditary ataxia (MONDO:0100309), intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (MONDO:0032883), neurodevelopmental disorder with hypotonia, seizures, and absent language (MONDO:0014995), NK-cell enteropathy (MONDO:0016996)

Orphanet (10): Syndromic craniosynostosis (Orphanet:139393), Autosomal dominant non-syndromic intellectual disability (Orphanet:178469), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), 2q23.1 microdeletion syndrome (Orphanet:228402), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Hereditary ataxia (Orphanet:183518), NK-cell enteropathy (Orphanet:263665), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008522_78	Bitter alcoholic beverage consumption	5.000000e-06
GCST90002398_88	Neutrophil count	7.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004833	neutrophil count

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C562568	Cerebellar Hypoplasia (supp.)
C531684	Hereditary spinal ataxia (supp.)
C566947	Mental Retardation, Autosomal Dominant 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	decreases expression, affects cotreatment	1
Quercetin	increases phosphorylation	1
Smoke	decreases expression	1
Thiram	increases expression	1
Valproic Acid	increases methylation	1
Zinc	increases expression	1
Cadmium Chloride	increases expression	1

Cellosaurus cell lines

11 cell lines: 10 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1NE	Abcam HeLa CIC KO	Cancer cell line	Female
CVCL_B7IM	BC-PAK1	Cancer cell line	Female
CVCL_F0ZN	GM29608	Induced pluripotent stem cell	Female
CVCL_SJ05	HAP1 CIC (-) 1	Cancer cell line	Male
CVCL_SJ06	HAP1 CIC (-) 2	Cancer cell line	Male
CVCL_SJ07	HAP1 CIC (-) 3	Cancer cell line	Male
CVCL_SJ08	HAP1 CIC (-) 4	Cancer cell line	Male
CVCL_YI69	Kitra-SRS	Cancer cell line	Female
CVCL_YL54	NCC-CDS1-X1-C1	Cancer cell line	Female
CVCL_YL55	NCC-CDS1-X3-C1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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)
NCT06213090	Not specified	RECRUITING	Patterns of Neurodevelopmental Disorders
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders