TCF12

Chr 15ADAR

transcription factor 12

Also known as: CRS3, HEB, HH26, HTF4, HsT17266, TCF-12, bHLHb20, p64

NCBI Gene: 6938ENSG00000140262UniProt: Q99081

The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH) E-protein family that recognizes the consensus binding site (E-box) CANNTG. This encoded protein is expressed in many tissues, among them skeletal muscle, thymus, B- and T-cells, and may participate in regulating lineage-specific gene expression through the formation of heterodimers with other bHLH E-proteins. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Craniosynostosis 3MIM #615314
AD
Hypogonadotropic hypogonadism 26 with or without anosmiaMIM #619718
ADAR
0
Active trials
141
Pathogenic / LP
459
ClinVar variants
37
Pubs (1 yr)
0.9
Missense Z
0.37
LOEUF
Clinical Summary— TCF12
🧬
Gene-Disease Validity (ClinGen)
TCF12-related craniosynostosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.68) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
141 Pathogenic / Likely Pathogenic· 240 VUS of 459 total submissions
📖
GeneReview available — TCF12
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.37LOEUF
pLI 0.676
Z-score 4.58
OE 0.21 (0.12–0.37)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.89Z-score
OE missense 0.87 (0.80–0.95)
338 obs / 387.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.21 (0.12–0.37)
0≤0.351.4
Missense OE0.87 (0.80–0.95)
0≤0.61.4
Synonymous OE1.15
0≤1.21.6
LoF obs/exp: 8 / 38.8Missense obs/exp: 338 / 387.3Syn Z: -1.40
LOF
DN
0.5476th %ile
GOF
0.2895th %ile
LOF
0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.37

Literature Evidence

LOFMutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosisPMID:23354436

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

ClinVar Variant Classifications

459 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic93
Likely Pathogenic48
VUS240
Likely Benign58
Benign13
Conflicting7
93
Pathogenic
48
Likely Pathogenic
240
VUS
58
Likely Benign
13
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
42
3
48
0
93
Likely Pathogenic
28
2
18
0
48
VUS
8
211
19
2
240
Likely Benign
0
15
22
21
58
Benign
0
2
6
5
13
Conflicting
—7
Total7823311328459

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

View in ClinVar →

TCF12 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TCF12-related neurodevelopmental disorder with coronal craniosynostosis

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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