CIC

Chr 19AD

capicua transcriptional repressor

Also known as: MRD45

NCBI Gene: 23152ENSG00000079432UniProt: Q96RK0

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. [provided by RefSeq, Feb 2015]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 45MIM #617600
AD
499
ClinVar variants
42
Pathogenic / LP
1.00
pLI score· haploinsufficient
12
Active trials
Clinical Summary— CIC
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 265 VUS of 499 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.18LOEUF
pLI 1.000
Z-score 6.02
OE 0.08 (0.04–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.73Z-score
OE missense 0.93 (0.88–0.99)
904 obs / 967.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.04–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.88–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.28
0≤1.21.6
LoF obs/exp: 4 / 49.9Missense obs/exp: 904 / 967.5Syn Z: -4.48

ClinVar Variant Classifications

499 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic25
VUS265
Likely Benign168
Benign13
Conflicting11
17
Pathogenic
25
Likely Pathogenic
265
VUS
168
Likely Benign
13
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
0
7
0
17
Likely Pathogenic
16
5
4
0
25
VUS
3
246
11
5
265
Likely Benign
0
63
16
89
168
Benign
0
2
2
9
13
Conflicting
—11
Total2931640103499

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CIC · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CIC-related neurodevelopmental disorder

strong
ADLoss Of FunctionAbsent Gene Product, Decreased Gene Product Level
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 45

MIM #617600

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.
Chang L et al.·Gastroenterology
2023Guideline
CIC-DUX4 sarcomas.
Brahmi M et al.·Curr Opin Oncol
2022Review
Translating genetic and functional data into clinical practice: a series of 223 families with myotonia.
Suetterlin K et al.·Brain
2022Cohort
American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.
Chang L et al.·Am J Gastroenterol
2023Guideline
Chronic idiopathic constipation in adults: epidemiology, pathophysiology, diagnosis and clinical management.
Black CJ et al.·Med J Aust
2018Review
Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis.
Suares NC et al.·Am J Gastroenterol
2011Meta-analysis
Evaluating the Impact of Cost on the Treatment Algorithm for Chronic Idiopathic Constipation: Cost-Effectiveness Analysis.
Shah ED et al.·Am J Gastroenterol
2021
Clinical characteristics and outcomes for children, adolescents and young adults with "CIC-fused" or "BCOR-rearranged" soft tissue sarcomas: A multi-institutional European retrospective analysis.
Sparber-Sauer M et al.·Cancer Med
2023
Tegaserod: What's Old Is New Again.
Sayuk GS et al.·Clin Gastroenterol Hepatol
2022Review
CIC-Related Neurodevelopmental Disorder: A Review of the Literature and an Expansion of Genotype and Phenotype.
Ruiz I et al.·Genes (Basel)
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
HivHBV Coinfection

Towards a Functional Cure for HBV - The COMMIT Cohort Study

ACTIVE NOT RECRUITING
NCT03645044University of MelbourneStarted 2018-05-24
Breast Cancer

Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery

ACTIVE NOT RECRUITING
NCT01349322Phase PHASE3Radiation Therapy Oncology GroupStarted 2011-05-24
Standard fractionation whole breast irradiationHypofractionated whole breast irradiationConcurrent boost
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Retinitis Pigmentosa

Promising ROd-cone DYstrophy Gene therapY

RECRUITING
NCT05748873Phase PHASE1, PHASE2SparingVisionStarted 2023-04-12
SPVN06
Humoral Primary Immunodeficiencies (PIDs)Secondary Form of Humoral ImmunodeficienciesCombined Immunodeficiency (CID)

Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency

RECRUITING
NCT06659588Assistance Publique - Hôpitaux de ParisStarted 2024-10-10
Plasma, urine and stool collection
Melanoma (Skin)

French Clinical Datbase of Melanoma Patients (RIC-Mel)

RECRUITING
NCT03315468Nantes University HospitalStarted 2012-03-01
ImmunologyAllergyGenetic Diseases

Impaired Type I IFN Immunity Due to Autoantibodies or a Genetic Defect: a Prospective National Cohort

RECRUITING
NCT06762002Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2025-04-09
blood sample
Heart Defects, Congenital

Genetics of Ventriculo-arterial Discordance

ACTIVE NOT RECRUITING
NCT05330338Phase NANantes University HospitalStarted 2022-09-07
Genetic analyses: whole genome sequencing
Prostate Cancer

Androgen-Deprivation Therapy and Radiation Therapy in Treating Patients With Prostate Cancer

ACTIVE NOT RECRUITING
NCT01368588Phase PHASE3Radiation Therapy Oncology GroupStarted 2011-07
radiation therapyWhole-pelvic radiotherapy (WPRT)
Breast Cancer

Evaluating the Addition of Adjuvant Chemotherapy to Ovarian Function Suppression Plus Endocrine Therapy in Premenopausal Patients With pN0-1, ER-Positive/HER2-Negative Breast Cancer and an Oncotype Recurrence Score Less Than or Equal to 25

RECRUITING
NCT05879926Phase PHASE3NRG OncologyStarted 2023-08-31
Ovarian Function Suppression + Aromatase InhibitorAdjuvant Chemotherapy + Ovarian Function Suppression
Prostate AdenocarcinomaStage III Prostate Cancer AJCC v8Stage IVA Prostate Cancer AJCC v8

Two Studies for Patients With High Risk Prostate Cancer Testing Less Intense Treatment for Patients With a Low Gene Risk Score and Testing a More Intense Treatment for Patients With a High Gene Risk Score, The PREDICT-RT Trial

ACTIVE NOT RECRUITING
NCT04513717Phase PHASE3NRG OncologyStarted 2021-01-21
ApalutamideBicalutamideBiospecimen Collection
Breast CancerCognitive Impairments

Cognitive Training for Cancer Related Cognitive Impairment in Breast Cancer Survivors

RECRUITING
NCT05896189Phase NANRG OncologyStarted 2024-04-12
Arm 1: Computerized Cognitive Training-Global Stimulation GamesArm 2: Computerized Cognitive Training-Neuroplasticity Games

External Resources

Links to major genomics databases and tools