CTCF

Chr 16AD

CCCTC-binding factor

Also known as: CFAP108, FAP108, MRD21

NCBI Gene: 10664 ENSG00000102974 UniProt: P49711 OMIM: 604167

CTCF encodes a chromatin binding factor with 11 zinc finger domains that regulates 3D chromatin structure, forms chromatin loops, and controls gene expression by binding to chromatin insulators and preventing interaction between promoters and enhancers. Heterozygous mutations cause autosomal dominant intellectual developmental disorder. This gene is highly constrained against loss-of-function variants, indicating that such variants are likely pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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

121 unique Pathogenic / Likely Pathogenic· 176 VUS of 424 total submissions

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Clinical Trials

2 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 OE0.03 (0.01–0.15)

0≤0.351.4

Missense OE0.40 (0.35–0.45)

0≤0.61.4

Synonymous OE1.14

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

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 · 42% of P/LP variants are LoF · LOEUF 0.15

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.PMID:34657170

LOFWhile CTCF is essential for cell survival, CTCF haploinsufficiency is associated with tumour development and hypermethylation.PMID:32816606

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