CTCF

Chr 16AD

CCCTC-binding factor

Also known as: CFAP108, FAP108, MRD21

NCBI Gene: 10664ENSG00000102974UniProt: P49711OMIM: 604167

This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms' tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

GeneReviewsOMIMResearchGenerating clinical summary…
LOFmechanismADLOEUF 0.151 OMIM phenotype
Clinical Summary— CTCF
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Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.
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ClinVar Variants
94 unique Pathogenic / Likely Pathogenic· 171 VUS of 391 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — CTCF
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?
0.15LOEUF
pLI 1.000
Z-score 5.08
OE 0.03 (0.01–0.15)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?
4.44Z-score
OE missense 0.40 (0.35–0.45)
174 obs / 434.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?
LoF OE?0.03 (0.01–0.15)
0≤0.351.4
Missense OE?0.40 (0.35–0.45)
0≤0.61.4
Synonymous OE?1.14
0≤1.21.6
LoF obs/exp: 1 / 32.0Missense obs/exp: 174 / 434.4Syn Z: -1.36
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCTCF-related intellectual disabilityLOFAD

This gene — mechanism propensity

DN
0.2997th %ile
GOF
0.2796th %ile
LOF
0.84top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 56% of P/LP variants are LoF · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity
GOF1 literature citation

Literature Evidence

GOFOur data confirm that a spectrum of loss-, change- and gain-of-function impacts on CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities.1
LOFWhile CTCF is essential for cell survival, CTCF haploinsufficiency is associated with tumour development and hypermethylation.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 34657170 ↗
  2. 2.PMID 32816606 ↗

ClinVar Variant Classifications

391 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic54
VUS171
Likely Benign71
Benign21
Conflicting15
40
Pathogenic
54
Likely Pathogenic
171
VUS
71
Likely Benign
21
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
9
0
0
40
Likely Pathogenic
22
32
0
0
54
VUS
2
164
4
1
171
Likely Benign
0
10
18
43
71
Benign
0
0
18
3
21
Conflicting
—15
Total552154047372

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap CTCF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

CTCF · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients