TCF7L2

Summary

TCF7L2 (transcription factor 7 like 2, HGNC:11641) is a protein-coding gene on chromosome 10q25.2-q25.3, encoding Transcription factor 7-like 2 (Q9NQB0). Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner.

This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes. Several transcript variants encoding multiple different isoforms have been found for this gene.

Source: NCBI Gene 6934 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 193
• Clinical variants (ClinVar): 250 total — 6 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 171
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Transcription factor: yes — 117 downstream targets (CollecTRI)
• MANE Select transcript: NM_001367943

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11641
Approved symbol	TCF7L2
Name	transcription factor 7 like 2
Location	10q25.2-q25.3
Locus type	gene with protein product
Status	Approved
Aliases	TCF-4
Ensembl gene	ENSG00000148737
Ensembl biotype	protein_coding
OMIM	602228
Entrez	6934

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 53 protein_coding, 8 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000277945, ENST00000346198, ENST00000349937, ENST00000352065, ENST00000355717, ENST00000355995, ENST00000369386, ENST00000369389, ENST00000369395, ENST00000369397, ENST00000470254, ENST00000471569, ENST00000480888, ENST00000494353, ENST00000534894, ENST00000538897, ENST00000545257, ENST00000627217, ENST00000629706, ENST00000636236, ENST00000636309, ENST00000636447, ENST00000636585, ENST00000637321, ENST00000637416, ENST00000637574, ENST00000704414, ENST00000704415, ENST00000704420, ENST00000704421, ENST00000704422, ENST00000867562, ENST00000867563, ENST00000867564, ENST00000867565, ENST00000867566, ENST00000867567, ENST00000867568, ENST00000867569, ENST00000867570, ENST00000867571, ENST00000867572, ENST00000867573, ENST00000867574, ENST00000867575, ENST00000867576, ENST00000867577, ENST00000867578, ENST00000867579, ENST00000867580, ENST00000867581, ENST00000867582, ENST00000867583, ENST00000867584, ENST00000867585, ENST00000928214, ENST00000928215, ENST00000928216, ENST00000928217, ENST00000928218, ENST00000949137, ENST00000949138, ENST00000949139, ENST00000949140

RefSeq mRNA: 17 — MANE Select: NM_001367943 NM_001146274, NM_001146283, NM_001146284, NM_001146285, NM_001146286, NM_001198525, NM_001198526, NM_001198527, NM_001198528, NM_001198529, NM_001198530, NM_001198531, NM_001349870, NM_001349871, NM_001363501, NM_001367943, NM_030756

CCDS: CCDS53577, CCDS53578, CCDS55729, CCDS73196, CCDS73197, CCDS73198, CCDS7576, CCDS81504, CCDS86148, CCDS91348, CCDS91349, CCDS91350

Canonical transcript exons

ENST00000355995 — 15 exons

Exon	Start	End
ENSE00000987139	112964556	112964624
ENSE00001699148	113150998	113151123
ENSE00002258101	112950247	112950945
ENSE00003496147	112951483	112951607
ENSE00003517323	113151725	113151884
ENSE00003524030	113152333	113152440
ENSE00003527108	113146011	113146097
ENSE00003590241	113158667	113158717
ENSE00003601851	113159920	113159992
ENSE00003620069	113158021	113158069
ENSE00003644651	112951207	112951273
ENSE00003644692	113143923	113144025
ENSE00003656283	113165555	113167678
ENSE00003734737	113040025	113040126
ENSE00003789188	113141184	113141316

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4417 / max 221.6467, expressed in 1496 samples.

FANTOM5 promoters (37 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107074	35.5500	1743
107077	13.8650	1565
172075	10.4417	1496
172069	3.2584	667
107079	3.0757	1153
107078	2.2086	960
172078	1.9778	685
107075	1.3316	733
172028	1.1333	453
107073	1.0269	587

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.81	gold quality
endothelial cell	CL:0000115	99.45	gold quality
pancreatic ductal cell	CL:0002079	99.41	gold quality
hair follicle	UBERON:0002073	99.33	gold quality
decidua	UBERON:0002450	98.81	gold quality
epithelium of mammary gland	UBERON:0003244	98.75	gold quality
mammary duct	UBERON:0001765	98.72	gold quality
tibia	UBERON:0000979	98.63	gold quality
visceral pleura	UBERON:0002401	98.59	gold quality
germinal epithelium of ovary	UBERON:0001304	98.39	gold quality
parietal pleura	UBERON:0002400	98.37	gold quality
pleura	UBERON:0000977	98.30	gold quality
jejunal mucosa	UBERON:0000399	98.23	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.14	gold quality
saphenous vein	UBERON:0007318	98.09	gold quality
colonic mucosa	UBERON:0000317	98.01	gold quality
skin of hip	UBERON:0001554	97.97	gold quality
synovial joint	UBERON:0002217	97.90	gold quality
cauda epididymis	UBERON:0004360	97.82	gold quality
palpebral conjunctiva	UBERON:0001812	97.80	gold quality
periodontal ligament	UBERON:0008266	97.65	gold quality
blood vessel layer	UBERON:0004797	97.47	gold quality
urethra	UBERON:0000057	97.43	gold quality
mammary gland	UBERON:0001911	97.40	gold quality
thoracic mammary gland	UBERON:0005200	97.37	gold quality
seminal vesicle	UBERON:0000998	97.31	gold quality
adult organism	UBERON:0007023	97.15	gold quality
eye	UBERON:0000970	97.07	gold quality
epithelial cell of pancreas	CL:0000083	97.01	gold quality
sural nerve	UBERON:0015488	96.86	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	244.52
E-HCAD-35	yes	62.33
E-ANND-3	yes	24.84
E-GEOD-93593	yes	15.20
E-CURD-112	yes	4.21
E-HCAD-5	no	3043.96
E-MTAB-7249	no	473.66
E-MTAB-6911	no	366.13

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

117 targets.

Target	Regulation
ABCB1	Unknown
ABCD2	Unknown
ACVRL1	Unknown
AKT1	Activation
AKT2	Unknown
AMHR2	Activation
APCDD1	Activation
AXIN1	Activation
AXIN2	Activation
BACE1	Repression
BAMBI	Activation
BCL2	Activation
BCL2L2	Activation
BIRC5	Activation
BIRC7	Activation
BMP2	Unknown
BOK	Repression
CAPN2	Activation
CASP3	Repression
CASP7	Repression
CCL2	Activation
CCN1
CCN2	Activation
CCND1	Unknown
CD24
CD44	Activation
CDKN2A	Repression
CDX1	Activation
CDX2	Activation
CLDN1	Activation

JASPAR motifs

Motif	Name	Family
MA0523.1	TCF7L2	TCF-7-related factors
MA0523.2	TCF7L2	TCF-7-related factors

JASPAR matrix evidence (PMIDs): PMID:18268006

Upstream regulators (CollecTRI, top): AR, EGR1, FOXA2, GATA3, HNF4A, PAX6, SMAD1, STAT3, TP53

miRNA regulators (miRDB)

163 targeting TCF7L2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-493-5P	99.96	72.47	2382

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• tcf4 can specifically recognize beta-catenin using alternative conformations (PMID:11713475)
• crystal structure of a human Tcf4-beta-catenin complex; comparison with recent structures of beta-catenin in complex with Xenopus Tcf3 (XTcf3) and mammalian E-cadherin (PMID:11713476)
• Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin. (PMID:11931652)
• Activation of AXIN2 expression by beta-catenin-T cell factor (PMID:11940574)
• ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation (PMID:12086873)
• role of TCF-4 upon transcription of the human immunodeficiency virus type 1 (HIV-1) promoter in human astrocytic cells (PMID:12368361)
• The high expression level of hTcf-4 in HCC, especially with metastasis, suggests that the over-expression of hTcf-4 gene may be closely associated with development and progression of HCC, but the mutation of this gene plays a less important role (PMID:12378619)
• disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. (PMID:12408868)
• the C terminus of TCF4E cooperates with beta-catenin and p300 to form a specialized transcription factor complex that specifically supports the activation of the Cdx1 promoter (PMID:12446687)
• there is a direct interaction between the androgen receptor DNA binding domain (DBD) and Tcf4. (PMID:12799378)
• TCF-4N inhibits coactivation by beta-catenin of TCF/LEF transcription factors and potentiates the coactivation by beta-catenin of other transcription factors, such as SF-1 and C/EBPalpha (PMID:12861022)
• TCF4 could be an effective therapeutic target for suppressing the growth of hepatocellular cancers. (PMID:15040893)
• TCF4-binding element was identified in PTTG promoter region in eesophageal squamous cell sscarscinomsa. (PMID:15514942)
• identify selective beta-catenin binding hot spots of Tcf4, E-cadherin, and APC (PMID:15591320)
• Together, we suggest that quercetin is an excellent inhibitor of beta-catenin/Tcf signaling in SW480 cell lines, and the reduced beta-catenin/Tcf transcriptional activity is due to the decreased nuclear beta-catenin and Tcf-4 proteins. (PMID:15670774)
• TCF4 expression mediated by beta-catenin/p300 may be important for initial steps during trans-differentiation of endometrial carcinoma cells. (PMID:15806138)
• The regulation of GLCE expression by 2 cis-acting elements of the beta-catenin-TCF4 complex located in the enhancer region of the promoter are reported. (PMID:15853773)
• characterization of the TCF4 with microsatellite instability (MSI) in colon cancer and leukemia cell lines; results delineate a novel role for MSI+TCF4 in leukemia and colon cancer progression (PMID:15905022)
• the phosphorylation-dependent interaction between c-Jun and TCF4 regulates intestinal tumorigenesis by integrating JNK and APC/beta-catenin, two distinct pathways activated by WNT signalling (PMID:16007074)
• TIS7, a negative regulator of transcriptional activity, represses expression of OPN and beta-catenin/Tcf-4 target genes (PMID:16204248)
• The positive inter-regulation between beta-cat/Tcf-4 signaling and ET-1 signaling potentiates proliferation and survival of prostate cancer (CaP) cells, thereby representing a novel mechanism that contributes to CaP progression. (PMID:16291872)
• results suggest an established Wnt signaling pathway in most gastric cancers, a close correlation of beta-catenin/TCF4-mediated signaling with tumor dissemination, and the unlikelihood of a direct effect of activated Wnt signaling on CD44 expression (PMID:16311123)
• Suggestive linkage of type 2 diabetes mellitus to TCFL2 protein on chromosome 10q. (PMID:16415884)
• Represses Wnt signaling in breast tissue, and its downregulation contributes to the activation of Wnt signaling. (PMID:16532032)
• A role is suggested for TCF7L2 frameshift mutation during MSI-H colorectal tumor progression, by regulating the relative proportion of the different TCF7L2 isoforms. (PMID:16547505)
• Daxx reduced DNA binding activity of Tcf4 and repressed Tcf4 transcriptional activity. (PMID:16569639)
• findings suggest that activity at the HIV-1 promoter is influenced by phosphorylation of Sp1, which is affected by Tat and DNA-PK; interactions among TCF-4, Sp1 and/or Tat may determine the level of viral gene transcription in astrocytic cells (PMID:16690926)
• evidence provided that HIC1 antagonizes the TCF/beta-catenin-mediated transcription in Wnt-stimulated cells; this appears to be due to the ability of HIC1 to associate with TCF-4 and to recruit TCF-4 and beta-catenin to the HIC1 bodies (PMID:16724116)
• Common variants (rs12255372 and rs7903146) in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance (PMID:16855264)
• These data provide replicating evidence that variants in TCF7L2 increase the risk for type 2 diabetes and novel evidence that the variants likely influence both insulin secretion and insulin sensitivity. (PMID:16936218)
• These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes. (PMID:17003358)
• These data provide evidence that TCF7L2 is a major determinant of type 2 diabetes risk in European populations and suggests that this transcription factor plays a key role in glucose homeostasis. (PMID:17003360)
• Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. (PMID:17020404)
• Variants of the TCF7L2 gene contribute to the risk of type 2 diabetes. The population-attributable risk from this factor in the Dutch type 2 diabetes population is 10%. (PMID:17031610)
• crystallographic analysis of how beta-catenin, BCL9, BCL9-2 and Tcf4 interact (PMID:17052462)
• Although TCF7L2 is a major gene in type 2 diabetes, there is no evidence for association between this gene and type 1 diabetes. (PMID:17063324)
• TCF7L2 T at-risk allele variation predicts hyperglycemia incidence in a general French population, possibly through a deleterious effect on insulin secretion. (PMID:17065361)
• A high mobility group box-containing TCF7L2 leads to diabetes risk. (PMID:17091236)
• No major contribution of TCF7L2 sequence variants to maturity onset of diabetes of the young (MODY) or neonatal diabetes mellitus was found in this study in French white subjects. (PMID:17093940)
• TCF7L2 is an important gene for determining susceptibility to type 2 diabetes mellitus and it transgresses the boundaries of ethnicity. (PMID:17093941)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcf7l2	ENSDARG00000004415
mus_musculus	Tcf7l2	ENSMUSG00000024985
rattus_norvegicus	Tcf7l2	ENSRNOG00000049232

Paralogs (3): TCF7 (ENSG00000081059), LEF1 (ENSG00000138795), TCF7L1 (ENSG00000152284)

Protein

Protein identifiers

Transcription factor 7-like 2 — Q9NQB0 (reviewed: Q9NQB0)

Alternative names: HMG box transcription factor 4, T-cell-specific transcription factor 4

All UniProt accessions (17): Q9NQB0, A0A0A0MTL7, A0A0D9SGH8, A0A1B0GU84, A0A1B0GVE1, A0A994J4F0, A0A994J711, C6ZRJ7, C6ZRK5, E2GH26, H0YEE5, Q5JRY3, Q5JRY4, Q5VVR5, Q5VVR7, Q5VVR8, Q6FHW4

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as a repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5’-CCTTTGATC-3’ in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine.

Subunit / interactions. Interacts with TGFB1I1. Interacts with CTNNB1 (via the armadillo repeat); forms stable transcription complex. Interacts with EP300. Interacts with NLK. Interacts with CCDC85B (probably through the HMG box); prevents interaction with CTNNB1. Interacts with TNIK. Interacts with MAD2L2; prevents TCF7L2/TCF4 binding to promZIPK/DAPK3oters, negatively modulating its transcriptional activity. Interacts with ZIPK/DAPK3. Interacts with XIAP/BIRC4 and TLE3. Interacts with DDIT3/CHOP. The CTNNB1 and TCF7L2/TCF4 complex interacts with PML (isoform PML-4). Identified in a complex with CTNNB1 and FERMT2. Interacts with SPIN1. Interacts with C11orf84/SPINDOC in a SPIN1-dependent manner. Interacts with DAZAP2; the interaction results in localization of DAZAP2 to the nucleus.

Subcellular location. Nucleus. PML body.

Tissue specificity. Detected in epithelium from small intestine, with the highest expression at the top of the crypts and a gradient of expression from crypt to villus. Detected in colon epithelium and colon cancer, and in epithelium from mammary gland and carcinomas derived therefrom.

Post-translational modifications. In vitro, phosphorylated by TNIK. Phosphorylated at Thr-201 and/or Thr-212 by NLK. Phosphorylation by NLK at these sites inhibits DNA-binding by TCF7L2/TCF4, thereby preventing transcriptional activation of target genes of the canonical Wnt/beta-catenin signaling pathway. Polysumoylated. Sumoylation is enhanced by PIAS family members and desumoylation is enhanced by SENP2. Sumoylation/desumoylation regulates TCF7L2/TCF4 transcription activity in the Wnt/beta-catenin signaling pathway without altering interaction with CTNNB1 nor binding to DNA.

Disease relevance. Constitutive activation and subsequent transactivation of target genes may lead to the maintenance of stem-cell characteristics (cycling and longevity) in cells that should normally undergo terminal differentiation and constitute the primary transforming event in colorectal cancer (CRC). Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The promoter-specific activation domain interacts with the transcriptional coactivator EP300.

Miscellaneous. Low expression in pancreas and colon. Common splicing form, lowest expression in skeletal muscle. High transcriptional activity. Major isoform in liver.

Similarity. Belongs to the TCF/LEF family.

Isoforms (17)

UniProt ID	Names	Canonical?
Q9NQB0-1	1, TCF-4M	yes
Q9NQB0-2	2
Q9NQB0-3	3
Q9NQB0-4	4
Q9NQB0-5	5
Q9NQB0-6	6, TCF-4I
Q9NQB0-7	7
Q9NQB0-8	8
Q9NQB0-9	9, TCF-4G
Q9NQB0-10	10
Q9NQB0-11	11
Q9NQB0-12	12
Q9NQB0-13	13, TCF-4J
Q9NQB0-14	14, TCF-4B, short
Q9NQB0-15	15, TCF-4A
Q9NQB0-16	16, TCF-4K
Q9NQB0-17	17, TCF-4X2

RefSeq proteins (17): NP_001139746, NP_001139755, NP_001139756, NP_001139757, NP_001139758, NP_001185454, NP_001185455, NP_001185456, NP_001185457, NP_001185458, NP_001185459, NP_001185460, NP_001336799, NP_001336800, NP_001350430, NP_001354872, NP_110383 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR013558	CTNNB1-bd_N	Domain
IPR024940	TCF/LEF	Family
IPR027397	Catenin-bd_sf	Homologous_superfamily
IPR036910	HMG_box_dom_sf	Homologous_superfamily

Pfam: PF00505, PF08347

UniProt features (66 total): splice variant 16, mutagenesis site 15, compositionally biased region 9, region of interest 8, sequence conflict 6, cross-link 3, modified residue 2, sequence variant 2, helix 2, chain 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1JDH	X-RAY DIFFRACTION	1.9
1JPW	X-RAY DIFFRACTION	2.5
2GL7	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQB0-F1	53.78	0.10

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 201, 212, 22, 320, 539

Mutagenesis-validated functional residues (15):

Position	Phenotype
10–11	reduces ctnnb1 binding.
16	abolishes ctnnb1 binding.
17	reduces ctnnb1 binding.
19	reduces transcription activation.
21	reduces transcription activation.
23–24	reduces ctnnb1 binding.
24	reduces ctnnb1 binding, and abolishes ctnnb1 binding; when associated with a-26; a-28 and a-29.
26	abolishes ctnnb1 binding; when associated with a-24; a-28 and a-29.
28	abolishes ctnnb1 binding; when associated with a-24; a-26 and a-29.
29	reduces ctnnb1 binding, and abolishes ctnnb1 binding; when associated with a-24; a-26 and a-28.
48	abolishes ctnnb1 binding.
201	reduced phosphorylation by nlk and enhanced dna-binding; when associated with v-212.
212	reduced phosphorylation by nlk and enhanced dna-binding; when associated with v-201.
320	loss of sumoylation. no effect on localization to nuclear bodies.
322	loss of sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-4086398	Ca2+ pathway
R-HSA-4411364	Binding of TCF/LEF:CTNNB1 to target gene promoters
R-HSA-4641265	Repression of WNT target genes
R-HSA-5339700	Signaling by TCF7L2 mutants
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-8951430	RUNX3 regulates WNT signaling
R-HSA-9823730	Formation of definitive endoderm
R-HSA-9825892	Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
R-HSA-9909649	Regulation of PD-L1(CD274) transcription
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-2980736	Peptide hormone metabolism
R-HSA-3858494	Beta-catenin independent WNT signaling
R-HSA-392499	Metabolism of proteins
R-HSA-400508	Incretin synthesis, secretion, and inactivation
R-HSA-4791275	Signaling by WNT in cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9758941	Gastrulation

MSigDB gene sets: 1430 (showing top): AHRARNT_01, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_CHROMOSOME_ORGANIZATION, CREL_01, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, RRAGTTGT_UNKNOWN, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, HNF3ALPHA_Q6, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_CELLULAR_RESPONSE_TO_LIPID, TTTGTAG_MIR520D, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION

GO Biological Process (26): negative regulation of transcription by RNA polymerase II (GO:0000122), blood vessel development (GO:0001568), regulation of transcription by RNA polymerase II (GO:0006357), response to glucose (GO:0009749), positive regulation of epithelial to mesenchymal transition (GO:0010718), positive regulation of heparan sulfate proteoglycan biosynthetic process (GO:0010909), pancreas development (GO:0031016), positive regulation of insulin secretion (GO:0032024), regulation of hormone metabolic process (GO:0032350), glucose homeostasis (GO:0042593), maintenance of DNA repeat elements (GO:0043570), fat cell differentiation (GO:0045444), negative regulation of gluconeogenesis (GO:0045721), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), myoblast fate commitment (GO:0048625), regulation of smooth muscle cell proliferation (GO:0048660), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), canonical Wnt signaling pathway (GO:0060070), negative regulation of androgen receptor signaling pathway (GO:0060766), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of protein localization to nucleus (GO:1900182), negative regulation of type B pancreatic cell apoptotic process (GO:2000675), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), Wnt signaling pathway (GO:0016055)

GO Molecular Function (16): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription corepressor binding (GO:0001222), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), nuclear receptor binding (GO:0016922), protein kinase binding (GO:0019901), sequence-specific DNA binding (GO:0043565), gamma-catenin binding (GO:0045295), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), armadillo repeat domain binding (GO:0070016), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), PML body (GO:0016605), protein-DNA complex (GO:0032993), beta-catenin-TCF7L2 complex (GO:0070369), catenin-TCF7L2 complex (GO:0071664), beta-catenin-TCF complex (GO:1990907)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	2
Signaling by WNT	2
Incretin synthesis, secretion, and inactivation	1
Beta-catenin independent WNT signaling	1
Formation of the beta-catenin:TCF transactivating complex	1
Degradation of beta-catenin by the destruction complex	1
Signaling by WNT in cancer	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX3	1
Gastrulation	1
MITF-M-dependent gene expression	1
Regulation of PD-L1(CD274) expression	1
Signal Transduction	1
RNA Polymerase II Transcription	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
protein binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
vasculature development	1
anatomical structure development	1
response to hexose	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
regulation of heparan sulfate proteoglycan biosynthetic process	1
heparan sulfate proteoglycan biosynthetic process	1
positive regulation of proteoglycan biosynthetic process	1
positive regulation of protein O-linked glycosylation	1
animal organ development	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
regulation of hormone levels	1
regulation of metabolic process	1
hormone metabolic process	1
carbohydrate homeostasis	1
DNA metabolic process	1
chromosome organization	1
cell differentiation	1
gluconeogenesis	1
regulation of gluconeogenesis	1
negative regulation of biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of small molecule metabolic process	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cell fate commitment	1
myoblast differentiation	1

Protein interactions and networks

STRING

3252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCF7L2	CTNNB1	P35222	998
TCF7L2	HNF4A	P41235	908
TCF7L2	SLC30A8	Q8IWU4	890
TCF7L2	CDKAL1	Q5VV42	885
TCF7L2	HHEX	Q03014	880
TCF7L2	HDAC1	Q13547	847
TCF7L2	KCNJ11	Q14654	839
TCF7L2	GIPR	P48546	802
TCF7L2	FTO	Q9C0B1	768
TCF7L2	GLP1R	P43220	752
TCF7L2	AXIN1	O15169	739
TCF7L2	IGF2BP2	Q9Y6M1	726
TCF7L2	MTNR1B	P49286	720
TCF7L2	KCNQ1	P51787	712
TCF7L2	CREB1	P16220	706

IntAct

172 interactions, top by confidence:

A	B	Type	Score
TCF7L2	CTNNB1	psi-mi:“MI:0407”(direct interaction)	0.970
CTNNB1	TCF7L2	psi-mi:“MI:0915”(physical association)	0.970
TCF7L2	CTNNB1	psi-mi:“MI:0915”(physical association)	0.970
TCF7L2	CTNNB1	psi-mi:“MI:0914”(association)	0.970
PARP1	XRCC6	psi-mi:“MI:0914”(association)	0.850
XRCC6	PARP1	psi-mi:“MI:0914”(association)	0.850
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
BCL9	CTNNB1	psi-mi:“MI:0915”(physical association)	0.720
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
FOXM1	CTNNB1	psi-mi:“MI:0915”(physical association)	0.670
TCF7L2	XRCC6	psi-mi:“MI:0915”(physical association)	0.660
XRCC6	TCF7L2	psi-mi:“MI:0915”(physical association)	0.660

BioGRID (351): TCF7L2 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), TCF7L2 (Affinity Capture-Western), TCF7L2 (Affinity Capture-Western), DAXX (Affinity Capture-Western), DAXX (Two-hybrid), TCF7L2 (Affinity Capture-Western), TCF7L2 (Reconstituted Complex), TCF7L2 (Reconstituted Complex), TCF7L2 (Affinity Capture-Western), TCF7L2 (Affinity Capture-Western), HBP1 (Affinity Capture-Western), TCF7L2 (Co-crystal Structure), TCF7L2 (Reconstituted Complex), TCF7L2 (Reconstituted Complex)

ESM2 similar proteins: A0JC51, A5ABV9, O08656, O09100, O18896, O57311, O60481, O73689, O95409, P09022, P10070, P19544, P22561, P23769, P23770, P23771, P23772, P23824, P25932, P46684, P49639, P49952, P54655, P55878, P70062, P70063, Q08DV0, Q0VGT2, Q15915, Q62520, Q62521, Q6DJQ6, Q6VVD7, Q6XP49, Q7TQ40, Q800Q5, Q8JJC0, Q91689, Q924A0, Q924Y4

Diamond homologs: A0A0G2JTZ2, A2TED3, A8WWH5, B1H349, B3DM43, O94993, O95416, P27782, P35711, P35712, P36389, P36390, P36393, P36394, P36396, P36402, P40645, P40647, P40656, P57073, P57074, P61259, P70062, P70063, P70064, P91943, Q00417, Q03256, Q04886, Q04892, Q05738, Q10666, Q28447, Q2PG84, Q32PP9, Q5RCU4, Q62563, Q62565, Q67EX7, Q69FB1

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
TNIK	up-regulates	TCF7L2	phosphorylation
RNF138	“down-regulates quantity by destabilization”	TCF7L2	polyubiquitination
NLK	“down-regulates quantity”	TCF7L2	phosphorylation
CTNNB1	“up-regulates activity”	TCF7L2	binding
NLK	down-regulates	TCF7L2	phosphorylation
CSNK2A1	“up-regulates activity”	TCF7L2	phosphorylation
CSNK2A2	“up-regulates activity”	TCF7L2	phosphorylation
TCF7L2	“down-regulates activity”	Adipogenesis	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Deactivation of the beta-catenin transactivating complex	5	12.9×	5e-03
TCF dependent signaling in response to WNT	7	9.2×	5e-03
Formation of the beta-catenin:TCF transactivating complex	6	8.0×	6e-03
Signaling by WNT	6	7.5×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	7	15.9×	5e-05
positive regulation of transcription initiation by RNA polymerase II	5	10.6×	7e-03
transcription by RNA polymerase II	15	8.3×	1e-07
anatomical structure morphogenesis	7	7.6×	4e-03
chromatin remodeling	9	5.1×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — COAD, COADREAD, HCC, READ.

Clinical variants and AI predictions

ClinVar

250 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	7
Uncertain significance	109
Likely benign	37
Benign	53

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
2226191	NM_001367943.1(TCF7L2):c.1180G>T (p.Glu394Ter)	Pathogenic
2297867	NM_001367943.1(TCF7L2):c.755_762del (p.Gln252fs)	Pathogenic
2499565	NM_001367943.1(TCF7L2):c.1144C>T (p.Gln382Ter)	Pathogenic
2503276	NM_001367943.1(TCF7L2):c.553-1G>A	Pathogenic
2503277	NM_001367943.1(TCF7L2):c.1219C>T (p.Arg407Ter)	Pathogenic
3630120	NM_001367943.1(TCF7L2):c.733_748delinsTCCGC (p.Leu245fs)	Pathogenic
1308651	NM_001367943.1(TCF7L2):c.1197del (p.Tyr400fs)	Likely pathogenic
1700132	NM_001367943.1(TCF7L2):c.723del (p.Tyr242fs)	Likely pathogenic
3454169	NM_001367943.1(TCF7L2):c.1161+1G>A	Likely pathogenic
4538623	NM_001367943.1(TCF7L2):c.1256C>T (p.Ala419Val)	Likely pathogenic
4632870	NM_001367943.1(TCF7L2):c.1231A>G (p.Met411Val)	Likely pathogenic
4813341	NM_001367943.1(TCF7L2):c.553-3538_685+1239del	Likely pathogenic
4820167	NM_001367943.1(TCF7L2):c.162del (p.Asn55fs)	Likely pathogenic

SpliceAI

4116 predictions. Top by Δscore:

Variant	Effect	Δscore
10:112950942:CGAGG:C	donor_loss	1.0000
10:112950943:GAG:G	donor_gain	1.0000
10:112950944:AGGTA:A	donor_loss	1.0000
10:112950945:GGTAG:G	donor_loss	1.0000
10:113040023:A:AG	acceptor_gain	1.0000
10:113040024:G:GA	acceptor_gain	1.0000
10:113040024:GT:G	acceptor_gain	1.0000
10:113040122:TTGTC:T	donor_gain	1.0000
10:113040124:GTC:G	donor_gain	1.0000
10:113040125:TC:T	donor_gain	1.0000
10:113040126:CG:C	donor_loss	1.0000
10:113040127:G:GA	donor_loss	1.0000
10:113040127:G:GG	donor_gain	1.0000
10:113040128:TA:T	donor_loss	1.0000
10:113040129:A:AG	donor_loss	1.0000
10:113040130:AGT:A	donor_loss	1.0000
10:113141182:A:AG	acceptor_gain	1.0000
10:113141183:G:GA	acceptor_gain	1.0000
10:113151120:GTTC:G	donor_gain	1.0000
10:113151121:TTC:T	donor_gain	1.0000
10:113151124:G:GG	donor_gain	1.0000
10:113151724:GAAA:G	acceptor_gain	1.0000
10:113151881:GAGG:G	donor_gain	1.0000
10:113151882:AGGG:A	donor_loss	1.0000
10:113151883:GG:G	donor_gain	1.0000
10:113151884:GG:G	donor_gain	1.0000
10:113151885:GT:G	donor_loss	1.0000
10:113152321:C:G	acceptor_gain	1.0000
10:113152331:AGT:A	acceptor_gain	1.0000
10:113152332:GTG:G	acceptor_gain	1.0000

AlphaMissense

4002 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:112950899:T:C	L48P	1.000
10:113151774:A:G	K351E	1.000
10:113151776:G:C	K351N	1.000
10:113151776:G:T	K351N	1.000
10:113151777:A:G	K352E	1.000
10:113151779:A:C	K352N	1.000
10:113151779:A:T	K352N	1.000
10:113151780:C:A	P353T	1.000
10:113151780:C:T	P353S	1.000
10:113151781:C:A	P353H	1.000
10:113151781:C:G	P353R	1.000
10:113151781:C:T	P353L	1.000
10:113151784:T:A	L354H	1.000
10:113151784:T:C	L354P	1.000
10:113151786:A:G	N355D	1.000
10:113151787:A:T	N355I	1.000
10:113151788:T:A	N355K	1.000
10:113151788:T:G	N355K	1.000
10:113151790:C:A	A356E	1.000
10:113151790:C:T	A356V	1.000
10:113151792:T:A	F357I	1.000
10:113151792:T:C	F357L	1.000
10:113151792:T:G	F357V	1.000
10:113151793:T:C	F357S	1.000
10:113151793:T:G	F357C	1.000
10:113151794:C:A	F357L	1.000
10:113151794:C:G	F357L	1.000
10:113151796:T:A	M358K	1.000
10:113151796:T:C	M358T	1.000
10:113151796:T:G	M358R	1.000

dbSNP variants (sampled 300 via entrez): RS1000006717 (10:113045628 A>G), RS1000023661 (10:113016272 G>A), RS1000030309 (10:113056832 G>T), RS1000035390 (10:113084846 A>C), RS1000044697 (10:113160329 C>T), RS1000075724 (10:113160104 CAG>C), RS1000085050 (10:113165530 A>G), RS1000087695 (10:113125708 G>C), RS1000091440 (10:113014803 A>G), RS1000091839 (10:113006018 A>C,T), RS1000095654 (10:113120405 G>A), RS1000133923 (10:113128805 G>A,C), RS1000134022 (10:113126454 T>C), RS1000153519 (10:113127310 C>T), RS1000160915 (10:113010396 G>A)

Disease associations

OMIM: gene MIM:602228 | disease phenotypes: MIM:209850, MIM:125853

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Definitive	Autosomal dominant
intellectual disability	Moderate	Autosomal dominant
congenital glaucoma	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (7): autism (MONDO:0005260), intellectual disability (MONDO:0001071), type 2 diabetes mellitus (MONDO:0005148), TCF7L2-related neurodevelopmental disorder (MONDO:0100525), complex neurodevelopmental disorder (MONDO:0100038), congenital glaucoma (MONDO:0020366), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

171 total (30 of 171 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000083	Renal insufficiency
HP:0000154	Wide mouth
HP:0000174	Abnormal palate morphology
HP:0000194	Open mouth
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000293	Full cheeks
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000378	Cupped ear
HP:0000391	Thickened helices
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000451	Triangular nasal tip
HP:0000454	Flared nostrils
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0000545	Myopia
HP:0000554	Uveitis
HP:0000572	Visual loss
HP:0000582	Upslanted palpebral fissure
HP:0000662	Nyctalopia
HP:0000687	Widely spaced teeth

GWAS associations

193 associations (top):

Study	Trait	p-value
GCST000012_3	Type 2 diabetes	2.000000e-34
GCST000024_9	Type 2 diabetes	1.000000e-08
GCST000025_4	Type 2 diabetes	1.000000e-48
GCST000027_1	Type 2 diabetes	2.000000e-10
GCST000028_8	Type 2 diabetes	1.000000e-48
GCST000047_1	Type 2 diabetes	5.000000e-12
GCST000049_2	Type 2 diabetes	5.000000e-08
GCST000167_6	Type 2 diabetes	3.000000e-23
GCST000277_7	Type 2 diabetes	6.000000e-16
GCST000277_8	Type 2 diabetes	9.000000e-30
GCST000383_6	Type 2 diabetes	8.000000e-12
GCST000478_5	Type 2 diabetes	1.000000e-30
GCST000568_4	Fasting blood glucose	1.000000e-08
GCST000569_2	Two-hour glucose challenge	1.000000e-07
GCST000712_26	Type 2 diabetes	2.000000e-51
GCST000753_4	Metabolic syndrome	7.000000e-07
GCST000798_1	Glycated hemoglobin levels	1.000000e-07
GCST000976_1	Type 2 diabetes	1.000000e-06
GCST001212_3	Proinsulin levels	2.000000e-20
GCST001326_1	Type 2 diabetes	2.000000e-15
GCST001526_4	Fasting blood insulin (BMI interaction)	3.000000e-06
GCST001527_21	Fasting blood glucose (BMI interaction)	2.000000e-14
GCST001527_22	Fasting blood glucose (BMI interaction)	7.000000e-13
GCST001550_11	Type 2 diabetes	2.000000e-40
GCST001550_6	Type 2 diabetes	4.000000e-21
GCST001759_4	Type 2 diabetes	1.000000e-35
GCST001809_1	Type 2 diabetes	3.000000e-19
GCST001809_11	Type 2 diabetes	3.000000e-35
GCST001809_14	Type 2 diabetes	2.000000e-38
GCST001809_16	Type 2 diabetes	9.000000e-75

EFO canonical traits (38, from GWAS)

EFO ID	Trait name
EFO:0004307	glucose tolerance test
EFO:0000195	metabolic syndrome
EFO:0004541	HbA1c measurement
EFO:0004467	insulin measurement
EFO:0004340	body mass index
EFO:0004297	clinical laboratory measurement
EFO:0004468	glucose measurement
EFO:0008000	peak insulin response measurement
EFO:0004318	smoking behavior
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008002	physical activity measurement
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0004695	intraocular pressure measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0004847	age at onset
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0009924	Drugs used in diabetes use measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004469	HOMA-B
EFO:0004531	urate measurement
EFO:0010348	cholesteryl ester 20:4 measurement
EFO:0005000	leptin measurement
EFO:0004346	neuroimaging measurement
EFO:0007796	parental longevity

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D006871	Hydrophthalmos	C11.250.480; C11.525.381.407.480; C16.131.384.480; C16.614.438
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3038511 (PROTEIN COMPLEX), CHEMBL3885511 (PROTEIN-PROTEIN INTERACTION), CHEMBL3885533 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

8 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12255372	Efficacy	3	sulfonamides;urea derivatives	Diabetes Mellitus;Type 2
rs290487	Efficacy	3	repaglinide	Diabetes Mellitus;Type 2
rs290487	Toxicity	3	tacrolimus	Liver transplantation
rs4132670	Toxicity	3	hydrochlorothiazide	Hypertension
rs4506565	Toxicity	3	hydrochlorothiazide	Hypertension
rs7903146	Toxicity	3	cyclosporine;sirolimus;tacrolimus	Kidney Transplantation;Liver transplantation
rs7903146	Efficacy	3	sulfonamides;urea derivatives
rs7917983	Toxicity	3	hydrochlorothiazide	Hypertension

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs290487	TCF7L2	3	2.00	2	tacrolimus;repaglinide
rs4132670	TCF7L2	3	2.50	1	hydrochlorothiazide
rs4506565	TCF7L2	3	2.50	1	hydrochlorothiazide
rs7903146	TCF7L2	3	4.75	2	sulfonamides;urea derivatives;cyclosporine;sirolimus;tacrolimus
rs7917983	TCF7L2	3	2.50	1	hydrochlorothiazide
rs12243326	TCF7L2		0.00	0
rs12255372	TCF7L2	3	3.00	1	sulfonamides;urea derivatives
rs11196205	TCF7L2		0.00	0

ChEMBL bioactivities

502 potent at pChembl≥5 of 532 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.09	IC50	81	nM	CHEMBL3934717
7.07	IC50	85	nM	CHEMBL3955823
7.00	IC50	100	nM	CHEMBL3934717
6.97	IC50	106	nM	CHEMBL3897759
6.95	IC50	113	nM	CHEMBL568799
6.93	IC50	118	nM	CHEMBL3940417
6.83	IC50	148	nM	CHEMBL568799
6.78	IC50	168	nM	CHEMBL3955823
6.77	IC50	169	nM	CHEMBL3965907
6.74	IC50	181	nM	CHEMBL3963724
6.74	IC50	184	nM	CHEMBL3935110
6.71	IC50	194	nM	CHEMBL3939175
6.71	IC50	193	nM	CHEMBL3959525
6.71	IC50	196	nM	CHEMBL3897759
6.69	IC50	203	nM	CHEMBL3958263
6.69	IC50	203	nM	CHEMBL3983546
6.69	IC50	204	nM	CHEMBL3959525
6.67	IC50	213	nM	CHEMBL565824
6.67	IC50	215	nM	CHEMBL566677
6.67	IC50	215	nM	CHEMBL567285
6.67	IC50	215	nM	CHEMBL3958263
6.67	IC50	213	nM	CHEMBL3935110
6.67	IC50	215	nM	CHEMBL3983546
6.66	IC50	217	nM	CHEMBL3953370
6.65	IC50	223	nM	CHEMBL3939175
6.65	IC50	223	nM	CHEMBL3895814
6.64	IC50	227	nM	CHEMBL3895814
6.64	IC50	229	nM	CHEMBL3970316
6.64	IC50	229	nM	CHEMBL3953013
6.63	IC50	236	nM	CHEMBL3938608
6.62	IC50	237	nM	CHEMBL570194
6.62	IC50	238	nM	CHEMBL3963724
6.61	IC50	245	nM	CHEMBL3931303
6.60	IC50	253	nM	CHEMBL3930638
6.60	IC50	249	nM	CHEMBL3940417
6.59	IC50	256	nM	CHEMBL569230
6.59	IC50	255	nM	CHEMBL3897769
6.59	IC50	255	nM	CHEMBL566462
6.58	IC50	266	nM	CHEMBL3931303
6.58	IC50	262	nM	CHEMBL566677
6.57	IC50	270	nM	CHEMBL577512
6.57	IC50	268	nM	CHEMBL3965907
6.56	IC50	273	nM	CHEMBL570194
6.55	IC50	284	nM	CHEMBL3897769
6.54	IC50	287	nM	CHEMBL3978183
6.54	IC50	291	nM	CHEMBL568800
6.54	IC50	292	nM	CHEMBL3970869
6.52	IC50	300	nM	CHEMBL1334062
6.52	IC50	305	nM	CHEMBL3895823
6.52	IC50	300	nM	CHEMBL569004

PubChem BioAssay actives

27 with measured affinity, of 68 total; 24 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-(4-chlorophenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	775767: Inhibition of human TCF4/ flag epitope-tagged beta-catenin (unknown origin) interaction transfected in human HCT116 cells after 24 hrs by beta-galactosidase/luciferase reporter gene assay	ic50	0.3000	uM
N-[2-(4-fluorophenyl)ethyl]-4-[[[6-methyl-2-(methylamino)quinazolin-4-yl]amino]methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	1.0000	uM
6-[2-(2H-tetrazol-5-yl)ethyl]-1,2-benzoxazol-3-one	1141067: Inhibition of beta-catenin/T cell factor (unknown origin)	ki	1.3500	uM
4-[[[2-(butylamino)quinazolin-4-yl]amino]methyl]-N-(4-fluorophenyl)benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	1.5000	uM
4-[[[2-(dimethylamino)-6-methylquinazolin-4-yl]amino]methyl]-N-[2-(4-fluorophenyl)ethyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	1.5000	uM
4-[[[2-(dimethylamino)-6-methylquinazolin-4-yl]amino]methyl]-N-[(4-fluorophenyl)methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	2.0000	uM
N-[2-(4-fluorophenyl)ethyl]-4-[[[6-methyl-2-(propylamino)quinazolin-4-yl]amino]methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	2.0000	uM
4-fluoro-N-[4-[[[2-(propylamino)quinazolin-4-yl]amino]methyl]phenyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	2.5000	uM
N-(6-chloro-3-pyridinyl)-4-[[[2-(dimethylamino)-6-methylquinazolin-4-yl]amino]methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	2.5000	uM
N-(6-chloro-3-pyridinyl)-4-[[[6-methyl-2-(propylamino)quinazolin-4-yl]amino]methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	2.5000	uM
4-[[[2-(dimethylamino)-6-methylquinazolin-4-yl]amino]methyl]-N-[1-[(4-fluorophenyl)methyl]piperidin-4-yl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	2.5000	uM
N-(4-fluorophenyl)-4-[[[2-(propylamino)quinazolin-4-yl]amino]methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.0000	uM
4-[[[2-(dimethylamino)quinazolin-4-yl]amino]methyl]-N-(4-fluorophenyl)benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.0000	uM
N-[4-[[[2-(ethylamino)quinazolin-4-yl]amino]methyl]phenyl]-4-fluorobenzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.0000	uM
4-[[[2-(dimethylamino)-6-methylquinazolin-4-yl]amino]methyl]-N-[(1S,2R)-2-phenylcyclopropyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.0000	uM
N-[1-[(4-fluorophenyl)methyl]piperidin-4-yl]-4-[[[6-methyl-2-(methylamino)quinazolin-4-yl]amino]methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.0000	uM
N-[1-[(4-fluorophenyl)methyl]piperidin-4-yl]-4-[[[6-methyl-2-(propylamino)quinazolin-4-yl]amino]methyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.0000	uM
1-hydroxy-5-[2-(2H-tetrazol-5-yl)ethyl]indazole	725535: Inhibition of human beta-casein/Tcf4 interaction after 1 hr by fluorescence polarization assay	ki	3.1000	uM
4-fluoro-N-[4-[[[2-(methylamino)quinazolin-4-yl]amino]methyl]phenyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.5000	uM
4-[[[2-(ethylamino)quinazolin-4-yl]amino]methyl]-N-(4-fluorophenyl)benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.5000	uM
4-[[[2-(ethylamino)-6-methylquinazolin-4-yl]amino]methyl]-N-[(1S,2R)-2-phenylcyclopropyl]benzamide	655991: Inhibition of beta-casein/TCF4 pathway expressed in HCT116 cells containing delta45S mutant after 24 hrs by luciferase reporter gene assay	ic50	3.5000	uM
1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	725538: Inhibition of human beta-casein/Tcf4 interaction after 1 hr by alphascreen assay	ki	3.7000	uM
7,19-dihydroxy-5,21-bis[(2S)-2-hydroxypropyl]-6,20-dimethoxy-12,14-dioxahexacyclo[13.8.0.02,11.03,8.04,22.018,23]tricosa-1,3(8),4,6,10,15,18(23),19,21-nonaene-9,17-dione	725538: Inhibition of human beta-casein/Tcf4 interaction after 1 hr by alphascreen assay	ki	5.9000	uM
2,3-bis(4-chlorophenyl)quinoxaline-6-carboxylic acid	725535: Inhibition of human beta-casein/Tcf4 interaction after 1 hr by fluorescence polarization assay	ki	8.8000	uM

CTD chemical–gene interactions

77 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	7
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	affects expression, decreases expression	2
Carbamazepine	affects expression	2
Cisplatin	affects cotreatment, decreases expression, increases reaction	2
Nickel	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
TL8-506	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases expression, increases abundance, affects cotreatment	1
bisphenol A	affects methylation	1
geraniol	decreases expression	1
titanium dioxide	increases expression	1
N,N-dimethylaniline	decreases expression	1
afimoxifene	increases expression	1
aflatoxin B2	affects methylation	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
AH 23848	affects cotreatment, decreases expression	1
6-isopropoxy-9-oxoxanthene-2-carboxylic acid	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
nickel acetate	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1

ChEMBL screening assays

22 unique, capped per target: 22 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1919781	Binding	Inhibition of GST-tagged T cell factor4/beta casein interaction assessed as reduction in alkaline phosphatase level	Neopetrosiquinones A and B, sesquiterpene benzoquinones isolated from the deep-water sponge Neopetrosia cf. proxima. — Bioorg Med Chem

Cellosaurus cell lines

17 cell lines: 11 cancer cell line, 3 embryonic stem cell, 2 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7E9	SEES3-1V human TCF7L2, clone1	Embryonic stem cell	Male
CVCL_A7F0	SEES3-1V human TCF7L2, clone2	Embryonic stem cell	Male
CVCL_A7F1	SEES3-1V human TCF7L2, clone3	Embryonic stem cell	Male
CVCL_A9WH	CTSC#1.1	Cancer cell line	Male
CVCL_A9WI	CTSC#1.2	Cancer cell line	Male
CVCL_A9WJ	CTSC#18	Cancer cell line	Female
CVCL_A9WU	CTSC#432	Cancer cell line	Male
CVCL_A9WW	CTSC#446	Cancer cell line	Female
CVCL_A9WY	CTSC#510	Cancer cell line	Female
CVCL_B7ZV	Abcam Raji TCF7L2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

595 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders