TCF7L2

Chr 10AD

transcription factor 7 like 2

Also known as: TCF-4, TCF4

NCBI Gene: 6934ENSG00000148737UniProt: Q9NQB0OMIM: 602228

The TCF7L2 protein is a transcription factor that participates in Wnt signaling and regulates gene expression including MYC, playing essential roles in epithelial stem cell maintenance and glucose homeostasis. Mutations cause autosomal dominant susceptibility to type 2 diabetes mellitus. This gene is highly constrained against loss-of-function variants (pLI 0.995, LOEUF 0.273), indicating that complete loss of protein function is likely incompatible with normal development.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.271 OMIM phenotype
Clinical Summary— TCF7L2
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · 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
43 unique Pathogenic / Likely Pathogenic· 110 VUS of 278 total submissions
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.27LOEUF
pLI 0.995
Z-score 4.73
OE 0.12 (0.06–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.40Z-score
OE missense 0.64 (0.57–0.72)
227 obs / 354.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.12 (0.06–0.27)
0≤0.351.4
Missense OE0.64 (0.57–0.72)
0≤0.61.4
Synonymous OE1.21
0≤1.21.6
LoF obs/exp: 4 / 33.5Missense obs/exp: 227 / 354.0Syn Z: -2.11
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTCF7L2-related developmental disorderLOFAD
DN
0.4587th %ile
GOF
0.3193th %ile
LOF
0.84top 5%

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

LOFprediction above median · 26% of P/LP variants are LoF · LOEUF 0.27

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

278 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic11
VUS110
Likely Benign39
Benign53
32
Pathogenic
11
Likely Pathogenic
110
VUS
39
Likely Benign
53
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
26
0
32
Likely Pathogenic
5
3
3
0
11
VUS
8
97
5
0
110
Likely Benign
0
12
3
24
39
Benign
1
5
45
2
53
Total201178226245

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

View in ClinVar →

Protein Context — Lollipop Plot

TCF7L2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
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