TCF20

Chr 22AD

transcription factor 20

NCBI Gene: 6942ENSG00000100207UniProt: Q9UGU0

Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression. It stimulates the activity of various transcriptional activators such as JUN, SP1, PAX6 and ETS1, suggesting a function as a coactivator

Primary Disease Associations & Inheritance

Developmental delay with variable intellectual impairment and behavioral abnormalitiesMIM #618430
AD
592
ClinVar variants
51
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— TCF20
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Gene-Disease Validity (ClinGen)
developmental delay with variable intellectual impairment and behavioral abnormalities · 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
51 Pathogenic / Likely Pathogenic· 329 VUS of 592 total submissions
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Clinical Trials
1 active or recruiting trial — 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.
0.10LOEUF
pLI 1.000
Z-score 7.32
OE 0.03 (0.01–0.10)
Highly constrained

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

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.
0.09Z-score
OE missense 0.99 (0.94–1.04)
1048 obs / 1056.2 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.0.03 (0.01–0.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.94–1.04)
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.1.20
0≤1.21.6
LoF obs/exp: 2 / 66.4Missense obs/exp: 1048 / 1056.2Syn Z: -3.14

ClinVar Variant Classifications

592 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic14
VUS329
Likely Benign183
Benign10
Conflicting19
37
Pathogenic
14
Likely Pathogenic
329
VUS
183
Likely Benign
10
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
20
0
17
0
37
Likely Pathogenic
6
0
8
0
14
VUS
1
307
21
0
329
Likely Benign
0
49
13
121
183
Benign
0
3
0
7
10
Conflicting
—19
Total2735959128592

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

View in ClinVar →

Protein Context — Lollipop Plot

TCF20 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TCF20-related developmental delay with variable intellectual impairment and behavioural abnormalities

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental delay with variable intellectual impairment and behavioral abnormalities

MIM #618430

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.
Vetrini F et al.·Genome Med
2019Case report
Tcf20 deficiency is associated with increased liver fibrogenesis and alterations in mitochondrial metabolism in mice and humans.
Córdoba-Jover B et al.·Liver Int
2023
Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex.
Dominguez G et al.·Genes (Basel)
2024Review
Germline mosaicism in TCF20-associated neurodevelopmental disorders: a case study and literature review.
Poquérusse J et al.·J Hum Genet
2025Review
Diagnosis and clinical presentation of two individuals with a rare TCF20 pathogenic variant.
Schneeweiss MR et al.·BMJ Case Rep
2022Case report
Association Between CYP2D7 and TCF20 Polymorphisms and Coronary Heart Disease.
Zhang W et al.·Cardiovasc Toxicol
2024
Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan-McDermid syndrome.
Mitz AR et al.·Clin Genet
2024Review
A previously unrecognized 22q13.2 microdeletion syndrome that encompasses TCF20 and TNFRSF13C.
Upadia J et al.·Am J Med Genet A
2018Review
Rare and de novo duplications containing TCF20 are associated with a neurodevelopmental disorder.
Lévy J et al.·Clin Genet
2022
De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth.
Schäfgen J et al.·Eur J Hum Genet
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A Boy with a Novel Variant in TCF20: An Expanded Phenotype and a Brief Review of the Literature.
Ziveri D et al.·Children (Basel)
2025🔓 Open AccessReview
M2-exo promote orthodontic bone remodeling via the MeCP2-TCF20-HDAC1 axis.
Chen M et al.·Stem Cell Res Ther
2025🔓 Open AccessFunctional
Regulation of Dendrite and Dendritic Spine Formation by TCF20.
Vinci E et al.·J Neurochem
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
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

External Resources

Links to major genomics databases and tools