TCF4

Chr 18AD

transcription factor 4

Also known as: CDG2T, E2-2, FCD2, FECD3, ITF-2, ITF2, PTHS, SEF-2

NCBI Gene: 6925ENSG00000196628UniProt: P15884

This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

Primary Disease Associations & Inheritance

Corneal dystrophy, Fuchs endothelial, 3MIM #613267
AD
Pitt-Hopkins syndromeMIM #610954
AD
181
ClinVar variants
46
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— TCF4
🧬
Gene-Disease Validity (ClinGen)
Pitt-Hopkins syndrome · 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
46 Pathogenic / Likely Pathogenic· 95 VUS of 181 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.22LOEUF
pLI 1.000
Z-score 5.44
OE 0.09 (0.05–0.22)
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.
4.10Z-score
OE missense 0.44 (0.39–0.50)
187 obs / 425.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.09 (0.05–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.44 (0.39–0.50)
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.0.97
0≤1.21.6
LoF obs/exp: 4 / 42.1Missense obs/exp: 187 / 425.1Syn Z: 0.28

ClinVar Variant Classifications

181 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic22
VUS95
Likely Benign39
Conflicting1
24
Pathogenic
22
Likely Pathogenic
95
VUS
39
Likely Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
5
5
0
24
Likely Pathogenic
10
8
4
0
22
VUS
1
82
12
0
95
Likely Benign
0
3
18
18
39
Benign
0
0
0
0
0
Conflicting
—1
Total25983918181

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

View in ClinVar →

Protein Context — Lollipop Plot

TCF4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TCF4-related Pitt-Hopkins syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

TCF4-related corneal dystrophy, fuchs endothelial

strong
ADUndeterminedUncertain
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Corneal dystrophy, Fuchs endothelial, 3

MIM #613267

Molecular basis of disorder known

Autosomal dominant

Pitt-Hopkins syndrome

MIM #610954

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TCF4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Blastic Plasmacytoid Dendritic Cell Neoplasm.
Jain A et al.·J Natl Compr Canc Netw
2023Review
Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.
Zollino M et al.·Clin Genet
2019Review
Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer.
Wang Y et al.·Cell Death Differ
2022
De novo mutations in moderate or severe intellectual disability.
Hamdan FF et al.·PLoS Genet
2014
Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.
McKnight D et al.·Hum Mutat
2022
EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma.
Liu Y et al.·Blood
2023
A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.
Zheng JH et al.·Cell Rep
2024
FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer.
Yang S et al.·Mol Cancer
2017
TSPAN1 promotes autophagy flux and mediates cooperation between WNT-CTNNB1 signaling and autophagy via the MIR454-FAM83A-TSPAN1 axis in pancreatic cancer.
Zhou C et al.·Autophagy
2021
The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic.
Kadosh E et al.·Nature
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
ID4 suppresses proliferation and macrophage polarization in esophageal carcinoma through interaction with TCF4.
Han T et al.·Mol Cancer Res
2026
TCF4 intronic CAG repeat length modulates the effect of ATXN3 on age at onset in spinocerebellar ataxia type 3.
Wan N et al.·J Adv Res
2026
Super-Enhancer-Driven TCF4 Orchestrates Neuroblastoma Metastasis by Sphingolipid-Dependent Membrane Remodeling and ITGB1-FAK Activation.
Lou E et al.·Neuro Oncol
2026Functional
Cardamonin attenuates osteoporosis progression and promotes osteogenic differentiation of bone mesenchymal stem cells by upregulating TCF4 expression.
Sun H et al.·Toxicol Appl Pharmacol
2026
MMSA-1 is regulated by Wnt/TCF4 and involved in multiple myeloma progression and invasion via RAS/RAF signaling pathway.
Meng S et al.·Ann Hematol
2026🔓 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
Fuchs DystrophyFuchs' Endothelial DystrophyFuchs' Endothelial Corneal Dystrophy of Bilateral Eyes

FECD-TRACE: Fuchs' Endothelial Corneal Dystrophy TRAjectory and Correlation With Genotype in the United Kingdom

RECRUITING
NCT06881771University College, LondonStarted 2024-02-01
Clinical phenotypingCTG18.1 Expansion Status Genotyping
Pitt Hopkins Syndrome

Phase 1/2 Study of MZ-1866, an AAV-9 Gene Therapy Delivered by Intracerebroventricular Injection to Participants With Pitt Hopkins Syndrome

RECRUITING
NCT07135050Phase PHASE1, PHASE2Mahzi TherapeuticsStarted 2025-12-19
MZ-1866
Corneal Dystrophies

Analysis of the Genotype/Phenotype Relationship in the Fuchs' Corneal Endothelial Dystrophy in France

RECRUITING
NCT05742321Centre Hospitalier Universitaire de Saint EtienneStarted 2024-08-08
GenotypingHistologyCollection of data

External Resources

Links to major genomics databases and tools