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CTCF
CCCTC-binding factor
CTCF encodes a transcription factor that organises the three-dimensional structure of chromosomes and regulates gene expression across the genome. The CTCF gene provides instructions for making CCCTC-binding factor, a protein critical to chromosome architecture and gene regulation.
CTCF is located on the long (q) arm of chromosome 16, at band 16q22.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 16 in the library →Overview
CTCF encodes CCCTC-binding factor, a highly conserved transcription regulator expressed in all human cell types. The protein acts as an architectural organiser of the genome, binding tens of thousands of sites across chromosomes to establish boundaries between active and inactive regions of DNA. These boundaries, often called insulators, prevent regulatory signals from one gene inappropriately influencing neighbouring genes.
CTCF plays a fundamental role in establishing three-dimensional chromosome structure by anchoring chromatin loops that bring distant genomic regions into physical proximity. This spatial organisation is essential for normal development, particularly in the nervous system where precise gene expression patterns guide brain formation. Loss of CTCF function disrupts these organisational frameworks, leading to abnormal gene regulation during critical developmental windows.
What the gene does
The CTCF protein functions as a sequence-specific DNA-binding factor that recognises and attaches to particular motifs scattered throughout the genome. Once bound, CTCF recruits additional proteins to establish chromatin loops and topologically associating domains, which are structural units that compartmentalise the genome into discrete regulatory neighbourhoods.
CTCF serves multiple regulatory roles beyond chromosome organisation. The protein acts as a transcriptional insulator, blocking enhancer elements from activating promoters across CTCF-bound boundaries. It also participates in X-chromosome inactivation in females, helping to silence one copy of the X chromosome in each cell. Additionally, CTCF influences DNA replication timing and maintains genomic imprinting patterns, where certain genes are expressed from only the maternal or paternal chromosome.
The protein's regulatory activity depends on its ability to recognise specific DNA sequences through its zinc finger domains and to interact with chromatin-modifying complexes. CTCF binding sites are often conserved across species, reflecting the protein's essential contributions to genome organisation and cellular identity throughout development.
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Chromosome location
CTCF is located on the long arm of chromosome 16 at position 22.1 (16q22.1). The gene spans approximately 55 kilobases of genomic DNA and contains 12 exons that are transcribed and spliced together to produce the mature messenger RNA template for protein synthesis.
Protein structure
The CTCF protein comprises 727 amino acids with a distinctive central array of eleven C2H2-type zinc fingers that mediate DNA binding. These zinc finger domains span amino acids 266 through 577 and include ten canonical C2H2-type zinc fingers (numbered 1 through 10) plus an eleventh atypical zinc finger (differing in its structural motif). Different combinations of these zinc fingers recognise diverse DNA sequence motifs, enabling CTCF to bind tens of thousands of genomic sites with varying specificity.
The protein contains three disordered regions that flank and interrupt the zinc finger array. The first disordered region spans amino acids 180-211, occurring N-terminal to the zinc finger array. A second disordered region extends from amino acids 573-677, positioned C-terminal to the zinc finger domains. A third disordered region occupies amino acids 689-717 near the protein's C-terminus. These intrinsically disordered regions are thought to mediate protein-protein interactions and provide regulatory flexibility.
Key variants
Pathogenic variants in CTCF typically arise as de novo (new) changes not inherited from either parent. Most disease-causing variants are loss-of-function changes that reduce the amount of functional protein produced, including nonsense variants that introduce premature stop signals and frameshift variants caused by small insertions or deletions. Missense variants affecting the zinc finger domains can also impair DNA-binding specificity. The majority of individuals with CTCF-related conditions carry heterozygous variants, meaning one altered copy and one functional copy of the gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1024C>T | p.Arg342Cys | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1025G>A | p.Arg342His | Pathogenic/Likely pathogenic | ★★☆☆ | CTCF-related neurodevelopmental disorder |
c.1102C>T | p.Arg368Cys | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1103G>A | p.Arg368His | Pathogenic/Likely pathogenic | ★★☆☆ | CTCF-related disorder |
c.1133C>T | p.Pro378Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1343G>A | p.Arg448Gln | Pathogenic | ★★☆☆ | CTCF-related neurodevelopmental disorder |
c.1670_1674del | p.Val556_Cys557insTer | Pathogenic | ★★☆☆ | not provided |
c.1699C>T | p.Arg567Trp | Pathogenic/Likely pathogenic | ★★☆☆ | CTCF-related neurodevelopmental disorder |
c.610dup | p.Thr204fs | Pathogenic | ★★☆☆ | not provided |
c.615_618del | p.Lys206fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in CTCF cause a neurodevelopmental disorder characterised by intellectual disability, developmental delay, and microcephaly (smaller than average head size). Affected individuals often present with speech difficulties, behavioural challenges, and variable growth concerns. Some individuals exhibit distinctive facial features or skeletal abnormalities such as cleft palate.
The condition follows an autosomal dominant inheritance pattern, meaning a single altered copy of CTCF is sufficient to cause features. Because most cases arise from de novo variants, recurrence risk for future siblings is generally less than 1% when the variant arose de novo, though a small possibility of parental gonadal mosaicism exists. The severity and specific features vary among affected individuals, likely reflecting differences in which CTCF functions are most disrupted by particular variants and the influence of other genetic and environmental factors.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CTCF variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
CTCF appears on multiple NHS Genomic Medicine Service gene panels reflecting its role in neurodevelopmental and structural anomalies. The gene holds green (diagnostic-grade evidence) classification on the Intellectual Disability panel and the Severe Microcephaly panel, indicating strong evidence supporting its clinical validity for these presentations. CTCF is also listed with green classification (indicating strong evidence) on the DDG2P (Developmental Disorders Genotype-to-Phenotype) resource and the Clefting panel. Additionally, the gene appears on the Fetal Anomalies panel with strong evidence classification, supporting its inclusion in prenatal genomic investigations when relevant features are identified.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is CTCF inherited?
CTCF-related conditions follow autosomal dominant inheritance, meaning a variant in one copy of the gene can cause features. Most affected individuals have a de novo variant that occurred for the first time in them, rather than inheriting it from a parent.
What does CTCF protein do in cells?
CTCF binds specific DNA sequences throughout the genome to organise chromosomes into three-dimensional loops and regulatory domains. This organisation controls which genes are active in different tissues and developmental stages, with particularly important roles in brain development.
Can CTCF variants affect more than the nervous system?
Yes, while neurodevelopmental features predominate, some individuals with CTCF variants have structural differences such as cleft palate or growth concerns. The range of features reflects CTCF's widespread role in genome organisation across multiple organ systems during development.