TCF21

Chr 6

transcription factor 21

Also known as: POD1, bHLHa23

NCBI Gene: 6943ENSG00000118526UniProt: O43680

TCF21 encodes a transcription factor of the basic helix-loop-helix family. The TCF21 product is mesoderm specific, and expressed in embryonic epicardium, mesenchyme-derived tissues of lung, gut, gonad, and both mesenchymal and glomerular epithelial cells in the kidney. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

40
ClinVar variants
15
Pathogenic / LP
0.83
pLI score
1
Active trials
Clinical Summary— TCF21
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · UDNo Known Disease Relationship

No known disease relationship

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
15 Pathogenic / Likely Pathogenic· 19 VUS of 40 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.52LOEUF
pLI 0.826
Z-score 2.22
OE 0.00 (0.00–0.52)
Moderately constrained

More LoF-intolerant than ~75% 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.
0.78Z-score
OE missense 0.78 (0.65–0.94)
79 obs / 101.1 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.0.00 (0.00–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.65–0.94)
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: 0 / 5.8Missense obs/exp: 79 / 101.1Syn Z: 0.17

ClinVar Variant Classifications

40 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
VUS19
Likely Benign2
Benign4
15
Pathogenic
19
VUS
2
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
15
0
15
Likely Pathogenic
0
0
0
0
0
VUS
0
19
0
0
19
Likely Benign
0
1
1
0
2
Benign
0
0
2
2
4
Total02018240

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

View in ClinVar →

Protein Context — Lollipop Plot

TCF21 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis.
Wirka RC et al.·Nat Med
2019
Nicotinamide N-methyltransferase mediates lipofibroblast-myofibroblast transition and apoptosis resistance.
Rehan M et al.·J Biol Chem
2023
USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction.
Kim MJ et al.·Cell Death Dis
2022
[Effect of TCF21 on proliferation, migration and vascular production of breast cancer cells].
Li PW et al.·Zhonghua Bing Li Xue Za Zhi
2019
DNMT3a-mediated methylation of TCF21/hnRNPA1 aggravates hepatic fibrosis by regulating the NF-κB signaling pathway.
Li L et al.·Pharmacol Res
2023
PHENOTYPIC SWITCHING OF VASCULAR SMOOTH MUSCLE CELLS: KEY MECHANISM IN ATHEROSCLEROSIS PROGRESSION.
Chigareva I et al.·Georgian Med News
2025Review
Expression of Transcription Factor 21 (TCF21) and Upregulation Its Level Inhibits Invasion and Metastasis in Esophageal Squamous Cell Carcinoma.
Chen Y et al.·Med Sci Monit
2018
Delivery of miR-654-5p via SonoVue Microbubble Ultrasound Inhibits Proliferation, Migration, and Invasion of Vascular Smooth Muscle Cells and Arterial Thrombosis and Stenosis through Targeting TCF21.
Wang T et al.·Oxid Med Cell Longev
2022
TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney.
Gooskens SL et al.·Oncotarget
2015
Transcription factor 21 gene and prognosis in a coronary population.
Santos MR et al.·Rev Port Cardiol
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
TCF21 promotes epithelial-to-mesenchymal transition and cytoskeleton reorganization in uterine development and endometriosis.
Zhu J et al.·Nat Commun
2026
TCF21-WNT5A axis drives metastasis of colorectal cancer via stromal-tumor cell communication.
Huang Q et al.·J Transl Med
2026
The Transcription Factor TCF21 is Necessary for Adoption of Cell Fates by Foxd1+ Stromal Progenitors during Kidney Development.
Finer G et al.·Am J Physiol Renal Physiol
2026
miR-124 orchestrates epicardial-mesenchymal transformation and paracrine cardiomyocyte maturation in epicardial-specific Tcf21-PKR1 knockout mice.
Arora H et al.·Stem Cells
2026
Targeting TCF21-TCF3 heterodimer in tumor-associated pericytes attenuates hematogenous metastasis by restoring pericyte gatekeeper function.
Yin W et al.·Cell Rep Med
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Incisional Ventral Hernia

Cytokine Response to Abdominal Wall Reconstruction

RECRUITING
NCT07422584Northwestern UniversityStarted 2026-02-03
Not applicable- observational study

External Resources

Links to major genomics databases and tools