GTF2I

Summary

GTF2I (general transcription factor IIi, HGNC:4659) is a protein-coding gene on chromosome 7q11.23, encoding General transcription factor II-I (P78347). Interacts with the basal transcription machinery by coordinating the formation of a multiprotein complex at the C-FOS promoter, and linking specific signal responsive activator complexes.

This gene encodes a phosphoprotein containing six characteristic repeat motifs. The encoded protein binds to the initiator element (Inr) and E-box element in promoters and functions as a regulator of transcription. This locus, along with several other neighboring genes, is deleted in Williams-Beuren syndrome. There are many closely related genes and pseudogenes for this gene on chromosome 7. This gene also has pseudogenes on chromosomes 9, 13, and 21. Alternatively spliced transcript variants encoding multiple isoforms have been observed.

Source: NCBI Gene 2969 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 82 total — 1 pathogenic
• Phenotypes (HPO): 186
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 27 downstream targets (CollecTRI)
• MANE Select transcript: NM_032999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4659
Approved symbol	GTF2I
Name	general transcription factor IIi
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	TFII-I, BAP-135, SPIN, BTKAP1, DIWS, IB291
Ensembl gene	ENSG00000263001
Ensembl biotype	protein_coding
OMIM	601679
Entrez	2969

Gene structure

Transcript identifiers

Ensembl transcripts: 111 — 95 protein_coding, 10 retained_intron, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000432143, ENST00000438130, ENST00000443166, ENST00000462915, ENST00000464471, ENST00000473333, ENST00000476035, ENST00000482232, ENST00000484840, ENST00000490431, ENST00000491325, ENST00000573035, ENST00000613513, ENST00000614048, ENST00000614986, ENST00000615596, ENST00000620631, ENST00000620879, ENST00000621040, ENST00000621640, ENST00000621734, ENST00000650807, ENST00000652150, ENST00000690345, ENST00000850946, ENST00000901261, ENST00000901262, ENST00000901263, ENST00000901264, ENST00000901265, ENST00000901266, ENST00000901267, ENST00000901268, ENST00000901269, ENST00000901270, ENST00000901271, ENST00000901272, ENST00000901273, ENST00000901274, ENST00000901275, ENST00000901276, ENST00000901277, ENST00000901278, ENST00000901279, ENST00000901280, ENST00000901281, ENST00000901282, ENST00000901283, ENST00000901284, ENST00000901285, ENST00000901286, ENST00000901287, ENST00000901288, ENST00000901289, ENST00000901290, ENST00000901291, ENST00000901292, ENST00000901293, ENST00000901294, ENST00000901295, ENST00000901296, ENST00000901297, ENST00000901298, ENST00000901299, ENST00000901300, ENST00000901301, ENST00000901302, ENST00000932146, ENST00000932147, ENST00000932148, ENST00000932149, ENST00000932150, ENST00000932151, ENST00000932152, ENST00000932153, ENST00000932154, ENST00000932155, ENST00000932156, ENST00000932157, ENST00000932158, ENST00000932159, ENST00000932160, ENST00000932161, ENST00000932162, ENST00000932163, ENST00000932164, ENST00000932165, ENST00000932166, ENST00000932167, ENST00000932168, ENST00000932169, ENST00000932170, ENST00000932171, ENST00000932172, ENST00000932173, ENST00000932174, ENST00000932175, ENST00000932176, ENST00000932177, ENST00000932178, ENST00000932179, ENST00000949269, ENST00000949270, ENST00000949271, ENST00000949272, ENST00000949273, ENST00000949274, ENST00000949275, ENST00000949276, ENST00000949277, ENST00000949278

RefSeq mRNA: 6 — MANE Select: NM_032999 NM_001163636, NM_001280800, NM_001518, NM_032999, NM_033000, NM_033001

CCDS: CCDS47614, CCDS5573, CCDS5574, CCDS5575, CCDS64680

Canonical transcript exons

ENST00000573035 — 35 exons

Exon	Start	End
ENSE00002633906	74690973	74691111
ENSE00002636840	74714857	74714916
ENSE00002638135	74758780	74758855
ENSE00002640260	74718879	74718941
ENSE00002646628	74716894	74716950
ENSE00002649258	74657718	74658068
ENSE00002678923	74759548	74760692
ENSE00002994829	74745883	74745941
ENSE00003011996	74743449	74743520
ENSE00003028525	74752090	74752170
ENSE00003041055	74738045	74738103
ENSE00003053416	74728786	74728896
ENSE00003055507	74730229	74730294
ENSE00003078062	74736500	74736683
ENSE00003083610	74733923	74733981
ENSE00003102037	74749025	74749090
ENSE00003113239	74751361	74751416
ENSE00003116292	74748015	74748116
ENSE00003137909	74746337	74746411
ENSE00003142247	74753094	74753177
ENSE00003162458	74735461	74735532
ENSE00003167463	74753846	74754029
ENSE00003180799	74744758	74744941
ENSE00003184719	74755509	74755537
ENSE00003189674	74749268	74749451
ENSE00003192189	74757959	74758000
ENSE00003206460	74756820	74756861
ENSE00003206513	74732479	74732662
ENSE00003715433	74700606	74700634
ENSE00003729385	74698961	74699095
ENSE00003732947	74689124	74689227
ENSE00003737541	74705164	74705218
ENSE00003740935	74700247	74700430
ENSE00003750821	74706390	74706433
ENSE00003753103	74711032	74711109

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 98.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.2078 / max 495.0200, expressed in 1815 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79098	33.7671	1807
79099	3.9396	1354
79102	1.4941	910
79101	0.9440	575
79100	0.6378	357
79104	0.4718	251
79103	0.3242	153
79096	0.2238	121
79105	0.2167	76
204482	0.1887	73

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	98.93	gold quality
colonic epithelium	UBERON:0000397	98.78	gold quality
sural nerve	UBERON:0015488	98.75	gold quality
ventricular zone	UBERON:0003053	98.70	gold quality
right uterine tube	UBERON:0001302	98.62	gold quality
adrenal tissue	UBERON:0018303	98.57	gold quality
right adrenal gland cortex	UBERON:0035827	98.44	gold quality
right lobe of thyroid gland	UBERON:0001119	98.33	gold quality
left lobe of thyroid gland	UBERON:0001120	98.29	gold quality
right adrenal gland	UBERON:0001233	98.29	gold quality
cortical plate	UBERON:0005343	98.13	gold quality
right ovary	UBERON:0002118	98.07	gold quality
body of pancreas	UBERON:0001150	98.05	gold quality
left ovary	UBERON:0002119	98.03	gold quality
metanephros cortex	UBERON:0010533	97.94	gold quality
left adrenal gland	UBERON:0001234	97.90	gold quality
skin of abdomen	UBERON:0001416	97.79	gold quality
left adrenal gland cortex	UBERON:0035825	97.78	gold quality
mucosa of stomach	UBERON:0001199	97.77	gold quality
ectocervix	UBERON:0012249	97.71	gold quality
endocervix	UBERON:0000458	97.70	gold quality
tibial nerve	UBERON:0001323	97.68	gold quality
skin of leg	UBERON:0001511	97.68	gold quality
minor salivary gland	UBERON:0001830	97.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.63	gold quality
left uterine tube	UBERON:0001303	97.43	gold quality
cerebellar hemisphere	UBERON:0002245	97.41	gold quality
body of uterus	UBERON:0009853	97.40	gold quality
gall bladder	UBERON:0002110	97.34	gold quality
cerebellar cortex	UBERON:0002129	97.33	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.02
E-MTAB-6524	no	189.82

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

27 targets.

Target	Regulation
ADAM2
AKAP12
BTK
CCND1
CCND2
CCND3
CD44
CD74
CISH
DNAAF4	Unknown
E2F2
ERVW-4
FOS	Activation
GSC	Activation
GTF2I
HBB
HPS4
HSPA5	Activation
ITSN1
KDR
POLR2F
SIRT1	Activation
SLU7
SMARCA4
SRC
TGFB1
UCN

Upstream regulators (CollecTRI, top): FOXO3, GSC, GTF2I, HDAC3

miRNA regulators (miRDB)

131 targeting GTF2I, 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-432-3P	100.00	67.86	705
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-1193	100.00	65.93	529
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548N	99.98	71.94	4170
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-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-568	99.98	69.86	2084

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• G-kinase I beta interacted specifically with TFII-I, an unusual transcriptional regulator that associates with multiple proteins to modulate both basal and signal-induced transcription (PMID:12082086)
• GTF2IRD1 and GTF2I have roles in causing deficits on visual spatial functioning (PMID:12865760)
• Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS. (PMID:14556246)
• TFII-I is required for optimal induction of Grp78 by ER stress (PMID:15664986)
• These results demonstrate that USF1/USF2 and TFII-I interact cooperatively at the upstream RBEIII element and are necessary for the induction of latent HIV-1 in response to T-cell activation signals. (PMID:15767439)
• human VEGFR-2 promoter is functionally counter-regulated by TFII-I and TFII-IRD1. (PMID:15941713)
• cGMP-dependent protein kinase Ibeta binds to TFII-I and IRAG through a common interaction motif (PMID:16166082)
• TFII-I is recruited to the cyclin D1 promoter and transcriptionally activates this gene. (PMID:16314517)
• TFII-I directly interacts with Bright through amino acids in Bright’s protein interaction domain (PMID:16738337)
• The data suggest that TFII-I and USF regulate chromatin structure accessibility and recruitment of transcription complexes in the beta-globin gene locus. (PMID:16943425)
• observations suggest a model in which TFII-I suppresses agonist-induced calcium entry by competing with TRPC3 for binding to phospholipase C-gamma (PMID:17023658)
• TFII-I, PARP1, and SFPQ proteins, each previously implicated in gene regulation, form a complex controlling transcription of DYX1C1. Allelic differences in the promoter or 5’UTR of DYX1C1 may affect factor binding and thus regulation of the gene. (PMID:18445785)
• Bioinformatics and microarray results were combined to identify TFII-I downstream targets in the vertebrate genome. (PMID:18579769)
• These results demonstrate an essential role of TFII-I bound at an upstream LTR element for viral replication. (PMID:18976654)
• analyzed promoter regions of TFII-I genes and described their additional exons, as well as tested tissue specificity of both previously reported and novel alternatively spliced isoforms (PMID:19111598)
• Results suggest that TFII-I appears to have distinct roles in distinct phases of the mammalian cell cycle. (PMID:19182516)
• these results provide an initial step in understanding the biological role of Itk-TFII-I signaling in T-cell function. (PMID:19701889)
• TFII-I plays an inhibitory role in regulating genes that are essential in osteogenesis and intersects with the bone-specific transcription factor Runx2 and the retinoblastoma protein, pRb. (PMID:19880526)
• functional hemizygosity for the GTF2I and GTF2IRD1 genes is the main cause of the neurocognitive profile and some aspects of the gestalt phenotype of Williams-Beuren syndrome (PMID:19897463)
• These data indicate that Gtf2i is involved in several aspects of embryonic development and the development of social neurocircuitry and that GTF2I haploinsufficiency could be a contributor to the hypersociability in WBS patients. (PMID:21328569)
• TFII-I may modulate the cellular functions of BRCA1. (PMID:21407215)
• Data show that Igh 3’ enhancer-bound OCA-B and promoter-bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. (PMID:21549311)
• These data indicate that an E-box motif (RBE1) within the core promoter in the long terminal repeat of HIV-1 is a bona fide binding site for the RBF-2 transcription factor complex USF1, USF2, and TFII-I. (PMID:21813151)
• Our findings suggest the GTF2i gene is important in the etiology of autism in individuals with this duplication and in non-duplication cases with severe social interaction problems and repetitive behaviors. (PMID:22048961)
• TFII-I gene deletion may explain the Williams-Beuren syndrome phenotype because it acts as a negative regulator of TRPC3 expression in human B lymphocytes. (PMID:22566418)
• GTF2I duplication results in separation anxiety in mice and humans (PMID:22578324)
• CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome; GTF2IRD1 and GTF2I are the main genes causing the cognitive defects (PMID:22608712)
• Results reveal novel mechanisms by which TFII-I and DBC1 can modulate cellular fate by affecting cell-cycle control as well as the homologous recombination pathway. (PMID:24231951)
• TFII-I bridges Proliferating Cell Nuclear Antigen and Polzeta to promote Translesion synthesis (PMID:24922507)
• GTF2I mutation correlated with better survival. (PMID:24974848)
• Findings implicate the GTF2I gene in the neurogenetic basis of social communication and social anxiety, both in Williams syndrome and among individuals in healthy populations (PMID:25429715)
• The GTF2I rs117026326 polymorphism is associated with anti-SSA-positive primary Sjogren’s syndrome. (PMID:25480810)
• A proportion of this transcriptional dysregulation is caused by dosage imbalances in GTF2I, which encodes a key transcription factor at 7q11.23 that is associated with the LSD1 repressive chromatin complex and silences its dosage-sensitive targets. (PMID:25501393)
• show that SUMOylation is critical for TFII-I to promote cell proliferation and colony formation. Our findings contribute to understanding the role of SUMOylation in liver cancer development (PMID:25869096)
• Rather than contributing positively to promoter activity, a putative initiator element at the transcription start site acts as a target for negative regulation imposed on the L4P promoter of human adenovirus Type 5 by cellular TFII-I. (PMID:25926634)
• Copy-number variation in the general transcription factor gene, GTF2I is associated with gene-dose-dependent anxiety in mouse models and in both Williams syndrome and Dup7. (PMID:26285132)
• Study demonstrates a significant association between SLE in Chinese Han population and the GTF2I rs117026326 T allele/GTF2IRD1 rs4717901 C allele. (PMID:26320362)
• A novel interaction between TFII-I and Mdm2 with a negative effect on TFII-I transcriptional activity has been documented. (PMID:26656605)
• The authors found that human adenovirus 5 infection or ectopic E4-ORF3 expression leads to SUMOylation of TFII-I that precedes a rapid decline in TFII-I protein levels. (PMID:26814176)
• A common polymorphism in the Williams syndrome gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. (PMID:26853120)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gtf2i	ENSMUSG00000060261
rattus_norvegicus	Gtf2i	ENSRNOG00000001479

Paralogs (18): GTF2IRD1 (ENSG00000006704), ZMYM2 (ENSG00000121741), ZMYM5 (ENSG00000132950), THAP12 (ENSG00000137492), ZMYM4 (ENSG00000146463), ZMYM3 (ENSG00000147130), ZMYM6 (ENSG00000163867), KIAA1958 (ENSG00000165185), GTF2IRD2B (ENSG00000174428), EPM2AIP1 (ENSG00000178567), GTF2IRD2 (ENSG00000196275), ZMYM1 (ENSG00000197056), QRICH1 (ENSG00000198218), FAM200C (ENSG00000221886), FAM200A (ENSG00000221909), SCAND3 (ENSG00000232040), ZBED5 (ENSG00000236287), FAM200B (ENSG00000237765)

Protein

Protein identifiers

General transcription factor II-I — P78347 (reviewed: P78347)

Alternative names: Bruton tyrosine kinase-associated protein 135, SRF-Phox1-interacting protein, Williams-Beuren syndrome chromosomal region 6 protein

All UniProt accessions (10): P78347, A0A494C013, A0A494C0Q7, A0A494C1K3, A0A8I5KVB5, C9J6M0, X5D2J9, X5D939, X5DNP5, X5DR09

UniProt curated annotations — full annotation on UniProt →

Function. Interacts with the basal transcription machinery by coordinating the formation of a multiprotein complex at the C-FOS promoter, and linking specific signal responsive activator complexes. Promotes the formation of stable high-order complexes of SRF and PHOX1 and interacts cooperatively with PHOX1 to promote serum-inducible transcription of a reporter gene deriven by the C-FOS serum response element (SRE). Acts as a coregulator for USF1 by binding independently two promoter elements, a pyrimidine-rich initiator (Inr) and an upstream E-box. Required for the formation of functional ARID3A DNA-binding complexes and for activation of immunoglobulin heavy-chain transcription upon B-lymphocyte activation.

Subunit / interactions. Homodimer (Potential). Interacts with SRF and PHOX1. Binds a pyrimidine-rich initiator (Inr) and a recognition site (E-box) for upstream stimulatory factor 1 (USF1). Associates with the PH domain of Bruton’s tyrosine kinase (BTK). May be a component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST, PHF21A/BHC80, ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Interacts with BTK and ARID3A. Interacts with isoform beta of PRKG1. Interacts with GPR50 (C-TERMINAL DOMAIN).

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous. Isoform 1 is strongly expressed in fetal brain, weakly in adult brain, muscle, and lymphoblasts and is almost undetectable in other adult tissues, while the other isoforms are equally expressed in all adult tissues.

Post-translational modifications. Transiently phosphorylated on tyrosine residues by BTK in response to B-cell receptor stimulation. Phosphorylation on Tyr-248 and Tyr-398, and perhaps, on Tyr-503 contributes to BTK-mediated transcriptional activation. Sumoylated.

Disease relevance. GTF2I is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of GTF2I may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.

Similarity. Belongs to the TFII-I family.

Isoforms (5)

UniProt ID	Names	Canonical?
P78347-1	1	yes
P78347-2	2
P78347-3	3
P78347-4	4
P78347-5	5

RefSeq proteins (6): NP_001157108, NP_001267729, NP_001509, NP_127492, NP_127493, NP_127494 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004212	GTF2I	Repeat
IPR016659	TF_II-I	Family
IPR036647	GTF2I-like_rpt_sf	Homologous_superfamily

Pfam: PF02946

UniProt features (120 total): cross-link 34, modified residue 24, helix 13, turn 11, strand 8, repeat 6, region of interest 5, sequence conflict 5, splice variant 4, mutagenesis site 4, compositionally biased region 2, initiator methionine 1, chain 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2D9B	SOLUTION NMR
2DN4	SOLUTION NMR
2ED2	SOLUTION NMR
2EJE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78347-F1	69.39	0.31

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 (58): 278, 298, 2, 19, 103, 130, 207, 210, 214, 248, 353, 398, 412, 450, 503, 517, 556, 558, 668, 674 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
248	abolishes btk-mediated transcriptional activation. abolishes btk-mediated phosphorylation and impairs btk-mediated trans
398	abolishes btk-mediated transcriptional activation. abolishes btk-mediated phosphorylation and impairs btk-mediated trans
460	no change on btk-mediated transcriptional activation.
503	impairs btk-mediated transcriptional activation. abolishes btk-mediated phosphorylation and impairs btk-mediated transcr

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 691 (showing top): BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, PAL_PRMT5_TARGETS_UP, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, CCATCCA_MIR432, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, HNF4_DR1_Q3, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT

GO Biological Process (3): transcription by RNA polymerase II (GO:0006366), negative regulation of angiogenesis (GO:0016525), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (6): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-templated transcription	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
DNA-binding transcription factor binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1656 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GTF2I	BTK	Q06187	887
GTF2I	ZMYM3	Q14202	859
GTF2I	USF1	P22415	849
GTF2I	ARHGAP35	Q9NRY4	829
GTF2I	ZMYM2	Q9UBW7	813
GTF2I	KDM1A	O60341	804
GTF2I	HYDIN	Q4G0P3	797
GTF2I	SRGAP2	O75044	796
GTF2I	GPRIN2	O60269	780
GTF2I	SRGAP3	O43295	775
GTF2I	CLIP2	Q9UDT6	773
GTF2I	HDAC1	Q13547	766
GTF2I	NPEPPS	P55786	763
GTF2I	UGT2B17	O75795	763
GTF2I	NBPF1	Q3BBV0	763

IntAct

198 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
YY1	TFPT	psi-mi:“MI:0914”(association)	0.740
BTK	GTF2I	psi-mi:“MI:0915”(physical association)	0.720
GTF2I	BTK	psi-mi:“MI:0915”(physical association)	0.720
BTK	GTF2I	psi-mi:“MI:0217”(phosphorylation reaction)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
E6	TAX1BP3	psi-mi:“MI:0914”(association)	0.650
BRCA1	GTF2I	psi-mi:“MI:0915”(physical association)	0.610
GTF2I	BRCA1	psi-mi:“MI:0915”(physical association)	0.610
GTF2I	BRCA1	psi-mi:“MI:0403”(colocalization)	0.610
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
MAD2L2	CBX5	psi-mi:“MI:0914”(association)	0.530
NHLH2	AP3B1	psi-mi:“MI:0914”(association)	0.530
SOST	KPNA4	psi-mi:“MI:0914”(association)	0.530
TIGD6	MTHFR	psi-mi:“MI:0914”(association)	0.530
LHFPL4	ATP5F1B	psi-mi:“MI:0914”(association)	0.530
E6	CASK	psi-mi:“MI:0914”(association)	0.520
E6	TAX1BP3	psi-mi:“MI:0914”(association)	0.520
Tax	TAX1BP3	psi-mi:“MI:0914”(association)	0.520
GTF2I	ZMYM3	psi-mi:“MI:0403”(colocalization)	0.510
GTF2I	ZMYM2	psi-mi:“MI:0403”(colocalization)	0.510
GTF2I	ZMYM3	psi-mi:“MI:2364”(proximity)	0.510

BioGRID (513): GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-RNA), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Biochemical Activity), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS), GTF2I (Affinity Capture-MS)

ESM2 similar proteins: A0A2R6X6S3, A7MB80, B4GT53, B7ZQJ9, E1JH25, G5EC37, K8ERR8, O44757, O61366, P06536, P08970, P13864, P15130, P20193, P25049, P26358, P34402, P50534, P70047, P70475, P78347, P97500, Q01538, Q08875, Q08876, Q09449, Q09663, Q12830, Q22811, Q22992, Q24K09, Q581T1, Q5U2Y1, Q60JJ0, Q6E3D4, Q6FRS1, Q7ZXG4, Q80TY4, Q8CFC2, Q8IRH5

Diamond homologs: A4IFA3, A7MB80, B7ZQJ9, P78347, Q5U2Y1, Q6EKJ0, Q86UP8, Q99NI3, Q9ESZ8, Q9JI57, Q9UHL9

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
GTF2I	“up-regulates quantity by expression”	HSPA5	“transcriptional regulation”
GTF2I	“up-regulates activity”	ARID3A	binding
GTF2I	“up-regulates activity”	USF2	binding
GTF2I	“up-regulates activity”	USF1	binding
GTF2I	“up-regulates activity”	KDM1A	binding
GTF2I	“up-regulates activity”	KDM1A	relocalization
Gbeta	up-regulates	GTF2I	phosphorylation
ERK1/2	up-regulates	GTF2I	phosphorylation
BTK	up-regulates	GTF2I	phosphorylation
GTF2I	up-regulates	PRRX1	binding
MAPK1	up-regulates	GTF2I	phosphorylation
MAPK3	up-regulates	GTF2I	phosphorylation
PRKG1	up-regulates	GTF2I	phosphorylation
JAK2	“up-regulates activity”	GTF2I	phosphorylation
BTK	“up-regulates activity”	GTF2I	phosphorylation
SRC	“up-regulates activity”	GTF2I	phosphorylation
GTF2IRD1	down-regulates	GTF2I
GTF2I	“up-regulates quantity by expression”	FOS	“transcriptional regulation”
GTF2I	“up-regulates quantity by expression”	GSC	“transcriptional regulation”
GTF2I	“up-regulates activity”	“Polycomb repressive complex 2”	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 207 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
VEGFR2 mediated cell proliferation	5	21.0×	3e-04
Signaling by FGFR1 in disease	5	10.8×	4e-03
mRNA Splicing	12	9.7×	1e-06
Processing of Capped Intron-Containing Pre-mRNA	15	9.1×	4e-08
Signaling by BRAF and RAF1 fusions	7	8.8×	1e-03
Regulation of RAS by GAPs	6	8.5×	4e-03
mRNA Splicing - Minor Pathway	5	8.2×	1e-02
mRNA Splicing - Major Pathway	18	7.2×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of fibroblast proliferation	6	10.0×	7e-03
mRNA transport	6	8.9×	9e-03
mRNA splicing, via spliceosome	16	8.2×	1e-07
negative regulation of translation	7	7.7×	7e-03
chromatin remodeling	13	5.3×	7e-04
RNA splicing	10	5.0×	7e-03
mRNA processing	11	4.9×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — THYM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	52
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
916130	NC_000007.13:g.73944168_74138459dup	Pathogenic

SpliceAI

4802 predictions. Top by Δscore:

Variant	Effect	Δscore
7:74689119:CACA:C	acceptor_loss	1.0000
7:74689120:A:AG	acceptor_gain	1.0000
7:74689120:ACAG:A	acceptor_gain	1.0000
7:74689120:ACAGG:A	acceptor_gain	1.0000
7:74689121:C:G	acceptor_gain	1.0000
7:74689121:CA:C	acceptor_loss	1.0000
7:74689122:A:AG	acceptor_gain	1.0000
7:74689122:AG:A	acceptor_gain	1.0000
7:74689122:AGG:A	acceptor_gain	1.0000
7:74689123:G:GC	acceptor_loss	1.0000
7:74689123:G:GG	acceptor_gain	1.0000
7:74689123:GG:G	acceptor_gain	1.0000
7:74689123:GGG:G	acceptor_gain	1.0000
7:74689224:CATG:C	donor_loss	1.0000
7:74689228:G:GA	donor_loss	1.0000
7:74689228:G:GG	donor_gain	1.0000
7:74689229:T:A	donor_loss	1.0000
7:74690969:GTAG:G	acceptor_loss	1.0000
7:74690970:TAGT:T	acceptor_loss	1.0000
7:74690971:A:AG	acceptor_gain	1.0000
7:74690971:A:T	acceptor_loss	1.0000
7:74690971:AGT:A	acceptor_gain	1.0000
7:74690972:G:A	acceptor_loss	1.0000
7:74690972:G:GA	acceptor_gain	1.0000
7:74690972:GT:G	acceptor_gain	1.0000
7:74690972:GTG:G	acceptor_gain	1.0000
7:74690972:GTGT:G	acceptor_gain	1.0000
7:74690972:GTGTA:G	acceptor_gain	1.0000
7:74691058:G:GT	donor_gain	1.0000
7:74691080:A:T	donor_gain	1.0000

AlphaMissense

6557 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:74689205:T:C	L26P	1.000
7:74689217:T:A	L30H	1.000
7:74689217:T:C	L30P	1.000
7:74690973:T:C	C34R	1.000
7:74690983:T:C	L37P	1.000
7:74691007:C:A	A45D	1.000
7:74691009:T:C	C46R	1.000
7:74691011:C:G	C46W	1.000
7:74691013:T:A	I47N	1.000
7:74691015:G:C	A48P	1.000
7:74691016:C:A	A48E	1.000
7:74691045:G:A	G58R	1.000
7:74691045:G:C	G58R	1.000
7:74691046:G:A	G58E	1.000
7:74691057:G:A	G62R	1.000
7:74691057:G:C	G62R	1.000
7:74691058:G:A	G62E	1.000
7:74691100:T:C	F76S	1.000
7:74699069:T:A	V116D	1.000
7:74730234:T:A	W354R	1.000
7:74730234:T:C	W354R	1.000
7:74730236:G:C	W354C	1.000
7:74730236:G:T	W354C	1.000
7:74730256:T:C	L361P	1.000
7:74730258:C:A	R362S	1.000
7:74730268:T:A	V365D	1.000
7:74732484:G:C	A376P	1.000
7:74732590:C:A	P411Q	1.000
7:74732601:G:A	G415R	1.000
7:74732601:G:C	G415R	1.000

dbSNP variants (sampled 300 via entrez): RS1000073094 (7:74675105 G>A), RS1000119497 (7:74687112 A>C), RS1000197518 (7:74690475 A>G), RS1000254818 (7:74718622 T>G), RS1000322207 (7:74668960 T>A), RS1000842545 (7:74693508 A>C), RS1001070241 (7:74691715 A>G), RS1001108272 (7:74662670 G>A,C,T), RS1001125961 (7:74688392 A>G), RS1001154261 (7:74703633 G>T), RS1001504448 (7:74659190 T>C), RS1001554958 (7:74658903 C>T), RS1001882514 (7:74656632 T>C), RS1002058364 (7:74664231 T>C,G), RS1002179744 (7:74665833 T>G)

Disease associations

OMIM: gene MIM:601679 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

186 total (30 of 186 shown, HPO-id order):

HPO	Term
HP:0000010	Recurrent urinary tract infections
HP:0000014	Abnormality of the bladder
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000025	Functional abnormality of male internal genitalia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000075	Renal duplication
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000093	Proteinuria
HP:0000121	Nephrocalcinosis
HP:0000125	Pelvic kidney
HP:0000147	Polycystic ovaries
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000179	Thick lower lip vermilion
HP:0000212	Gingival overgrowth
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002217_1	Sjögren’s syndrome	1.000000e-53
GCST002541_60	Menarche (age at onset)	5.000000e-12
GCST003604_1	Sjögren’s syndrome	1.000000e-15
GCST005752_2	Systemic lupus erythematosus	3.000000e-14
GCST006061_65	Atrial fibrillation	3.000000e-09
GCST006414_123	Atrial fibrillation	3.000000e-10
GCST006630_11	Diastolic blood pressure	2.000000e-09
GCST006979_127	Heel bone mineral density	5.000000e-11
GCST007611_11	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	5.000000e-11
GCST007615_25	C-reactive protein levels	3.000000e-08
GCST010242_355	HDL cholesterol levels	9.000000e-11
GCST011426_23	Systemic lupus erythematosus	2.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0006336	diastolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004458	C-reactive protein measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724693 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.03	Kd	94.5	nM	CHEMBL5653589
7.03	ED50	94.5	nM	CHEMBL5653589
5.56	Kd	2772	nM	CHEMBL3752910
5.56	ED50	2772	nM	CHEMBL3752910
5.12	Kd	7551	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 11 total; 3 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148473: Binding affinity to human GTF2I incubated for 45 mins by Kinobead based pull down assay	kd	0.0945	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148473: Binding affinity to human GTF2I incubated for 45 mins by Kinobead based pull down assay	kd	2.7718	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179229: Binding affinity against GTF2I (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	7.5510	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
trichostatin A	decreases expression, affects expression, affects cotreatment	3
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
W 7	decreases reaction, increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	decreases expression	1
cerous chloride	decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
celastrol	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	affects localization, decreases phosphorylation, affects activity, increases abundance, increases ADP-ribosylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	decreases phosphorylation	1
bisphenol AF	increases expression	1
Zoledronic Acid	increases expression	1
Vorinostat	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651515	Binding	Binding affinity to human GTF2I incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SQ72	HAP1 GTF2I (-) 1	Cancer cell line	Male
CVCL_XP44	HAP1 GTF2I (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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