GTF2A1

Summary

GTF2A1 (general transcription factor IIA subunit 1, HGNC:4646) is a protein-coding gene on chromosome 14q31.1, encoding Transcription initiation factor IIA subunit 1 (P52655). TFIIA is a component of the transcription machinery of RNA polymerase II and plays an important role in transcriptional activation. It is a selective cancer dependency (DepMap: 88.8% of cell lines).

Accurate transcription initiation on TATA-containing class II genes involves the ordered assembly of RNA polymerase II (POLR2A; MIM 180660) and several general initiation factors (summarized by DeJong and Roeder, 1993 [PubMed 8224848]). One of these factors is TFIIA, which when purified from HeLa extracts consists of 35-, 19-, and 12-kD subunits.

Source: NCBI Gene 2957 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 37 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 88.8% of screened cell lines
• MANE Select transcript: NM_015859

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4646
Approved symbol	GTF2A1
Name	general transcription factor IIA subunit 1
Location	14q31.1
Locus type	gene with protein product
Status	Approved
Aliases	TFIIA
Ensembl gene	ENSG00000165417
Ensembl biotype	protein_coding
OMIM	600520
Entrez	2957

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000298173, ENST00000434192, ENST00000553612, ENST00000556268, ENST00000865083

RefSeq mRNA: 3 — MANE Select: NM_015859 NM_001278940, NM_015859, NM_201595

CCDS: CCDS9873, CCDS9874

Canonical transcript exons

ENST00000553612 — 9 exons

Exon	Start	End
ENSE00002451507	81220489	81220959
ENSE00002479098	81175452	81180330
ENSE00003458636	81203900	81204104
ENSE00003479737	81201594	81201658
ENSE00003481671	81196108	81196241
ENSE00003577794	81197409	81197484
ENSE00003582484	81216413	81216514
ENSE00003584420	81185531	81185620
ENSE00003693464	81192519	81192839

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 94.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.2074 / max 1587.4265, expressed in 1818 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144305	19.5867	1799
144306	10.9215	1780
144304	4.9393	1668
144302	1.1707	774
144308	1.0789	675
144309	0.5862	342
144307	0.4471	185
144310	0.2809	131
144303	0.1961	88

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	94.48	gold quality
tibia	UBERON:0000979	94.24	gold quality
corpus epididymis	UBERON:0004359	94.14	gold quality
pons	UBERON:0000988	92.41	gold quality
trabecular bone tissue	UBERON:0002483	92.35	gold quality
jejunal mucosa	UBERON:0000399	92.31	gold quality
oral cavity	UBERON:0000167	92.20	gold quality
postcentral gyrus	UBERON:0002581	92.14	gold quality
caput epididymis	UBERON:0004358	92.04	gold quality
calcaneal tendon	UBERON:0003701	92.02	gold quality
tendon of biceps brachii	UBERON:0008188	91.99	gold quality
cauda epididymis	UBERON:0004360	91.97	gold quality
parietal pleura	UBERON:0002400	91.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.81	gold quality
tendon	UBERON:0000043	91.78	gold quality
upper leg skin	UBERON:0004262	91.75	gold quality
penis	UBERON:0000989	91.61	gold quality
adult organism	UBERON:0007023	91.59	gold quality
lateral globus pallidus	UBERON:0002476	91.58	gold quality
parietal lobe	UBERON:0001872	91.49	gold quality
substantia nigra pars compacta	UBERON:0001965	91.40	gold quality
medial globus pallidus	UBERON:0002477	91.32	gold quality
superficial temporal artery	UBERON:0001614	91.25	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.17	gold quality
globus pallidus	UBERON:0001875	91.11	gold quality
jejunum	UBERON:0002115	91.10	gold quality
biceps brachii	UBERON:0001507	90.89	gold quality
superior vestibular nucleus	UBERON:0007227	90.89	gold quality
germinal epithelium of ovary	UBERON:0001304	90.84	gold quality
seminal vesicle	UBERON:0000998	90.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.93
E-CURD-10	no	521.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
TBP	Unknown

Upstream regulators (CollecTRI, top): TAF1, TBP, TBPL1

miRNA regulators (miRDB)

315 targeting GTF2A1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 88.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• V96F substitution of a deamidated human GTF2A1 (TFIIA) peptide promotes T-cell activation in an in vitro model of Celiac disease inflammation. (PMID:12054857)
• spatial positioning of the DNA-bound activation domain is important for efficient activation, possibly by maximizing its interactions with the transcriptional machinery including the TBP-TFIIA-TFIIB-promoter quaternary complex (PMID:12538582)
• Results present the X-ray structures of human and yeast TATA box-binding protein /transcription factor IIA/DNA complexes at 2.1A and 1.9A resolution, respectively (PMID:12972251)
• transcription factor IIA may regulate the intracellular molecular state and the function of TATA-binding protein-like protein (TLP) through its property of binding to TLP (PMID:14570910)
• Transfected taspase 1 enhances cleavage of TFIIA, and RNA interference knockdown of endogenous taspase 1 diminishes cleavage of TFIIA in vivo. (PMID:16537915)
• TFIIA induces a conformational change within the TBP/TATA complex that enhances its stability under both in vitro and physiological salt conditions. (PMID:17681538)
• GTF2A1 alone, or GTF2A1 plus HAAO are excellent candidate biomarkers for detecting Ovarian cancer (PMID:19724865)
• Our results provide first evidence that Taspase1 processing affects TFIIA regulation of TFIID and suggest that Taspase1 processing of TFIIA is required to establish INR-selective core promoter activity in the presence of NC2. (PMID:25996597)
• The interaction of TBP-like protein with TFIIA is essential to suppress proteasome-dependent turnover of TBP-like protein (PMID:27696626)
• In a cohort of youth at risk for bipolar disorder, pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for bipolar disorder in vulnerable populations. (PMID:28291257)
• Data suggest that many TATA-box-containing promoters contain a TFIIA recognition element (IIARE) that activates transcription by increasing the recruitment of RNA polymerase II, TFIIA (TF2A1/TF2A2 subunits), TAF4, and P300. (TAF4 = TATA box binding protein (TBP)-associated factor, RNA polymerase II, C1; P300 = E1A binding protein p300) (PMID:28539359)
• De novo produced TFIIA is rapidly confined to the cytoplasm via an evolutionary conserved nuclear export signal (NES, amino acids 21VINDVRDIFL30), interacting with the nuclear export receptor Exportin-1/chromosomal region maintenance 1 (Crm1). (PMID:28992066)
• Proteolytic processing of TFIIA by Taspase1 was found to mask evolutionary conserved nuclear export signal, thereby promoting nuclear localization and transcriptional activation of TFIIA target genes, such as CDKN2A. (PMID:29097782)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gtf2a1	ENSDARG00000011000
mus_musculus	Gtf2a1	ENSMUSG00000020962
rattus_norvegicus	Gtf2a1	ENSRNOG00000004300
drosophila_melanogaster	TfIIA-L	FBGN0011289
caenorhabditis_elegans		WBGENE00004136

Paralogs (1): GTF2A1L (ENSG00000242441)

Protein

Protein identifiers

Transcription initiation factor IIA subunit 1 — P52655 (reviewed: P52655)

Alternative names: General transcription factor IIA subunit 1, TFIIAL, Transcription initiation factor TFIIA 42 kDa subunit

All UniProt accessions (2): P52655, J3KNC0

UniProt curated annotations — full annotation on UniProt →

Function. TFIIA is a component of the transcription machinery of RNA polymerase II and plays an important role in transcriptional activation. TFIIA in a complex with TBP mediates transcriptional activity.

Subunit / interactions. TFIIA is a heterodimer of the large unprocessed subunit 1 and a small subunit gamma. It was originally believed to be a heterotrimer of an alpha (p35), a beta (p19) and a gamma subunit (p12). TFIIA forms a complex with TBP. Part of TBP-based Pol II pre-initiation complex (PIC), in which Pol II core assembles with general transcription factors and other specific initiation factors including GTF2E1, GTF2E2, GTF2F1, GTF2F2, TCEA1, ERCC2, ERCC3, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2A1, GTF2A2, GTF2B and TBP; this large multi-subunit PIC complex mediates DNA unwinding and targets Pol II core to the transcription start site where the first phosphodiester bond forms.

Subcellular location. Nucleus.

Post-translational modifications. The alpha and beta subunits are postranslationally produced from the precursor form by TASP1. The cleavage promotes proteasomal degradation.

Similarity. Belongs to the TFIIA subunit 1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P52655-1	42 kDa	yes
P52655-2	37 kDa

RefSeq proteins (3): NP_001265869, NP_056943, NP_963889 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004855	TFIIA_asu/bsu	Family
IPR009088	TFIIA_b-brl	Homologous_superfamily

Pfam: PF03153

UniProt features (42 total): mutagenesis site 13, modified residue 5, strand 5, chain 3, helix 3, region of interest 3, compositionally biased region 3, binding site 2, sequence variant 2, initiator methionine 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

52 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1NVP	X-RAY DIFFRACTION	2.1
5M4S	X-RAY DIFFRACTION	2.38
7NVU	ELECTRON MICROSCOPY	2.5
7NVS	ELECTRON MICROSCOPY	2.8
7NVT	ELECTRON MICROSCOPY	2.9
8S52	ELECTRON MICROSCOPY	2.9
7ZWD	ELECTRON MICROSCOPY	3
7ZX8	ELECTRON MICROSCOPY	3
8S51	ELECTRON MICROSCOPY	3.1
7ZWC	ELECTRON MICROSCOPY	3.2
7EGB	ELECTRON MICROSCOPY	3.3
7ZX7	ELECTRON MICROSCOPY	3.4
8S5N	ELECTRON MICROSCOPY	3.4
7ZXE	ELECTRON MICROSCOPY	3.5
7EG9	ELECTRON MICROSCOPY	3.7
8BZ1	ELECTRON MICROSCOPY	3.8
5IYB	ELECTRON MICROSCOPY	3.9
5IYC	ELECTRON MICROSCOPY	3.9
5IYD	ELECTRON MICROSCOPY	3.9
7EGC	ELECTRON MICROSCOPY	3.9
8BVW	ELECTRON MICROSCOPY	4
7EGA	ELECTRON MICROSCOPY	4.1
8BYQ	ELECTRON MICROSCOPY	4.1
8GXS	ELECTRON MICROSCOPY	4.16
7EDX	ELECTRON MICROSCOPY	4.5
7NVR	ELECTRON MICROSCOPY	4.5
7LBM	ELECTRON MICROSCOPY	4.8
8GXQ	ELECTRON MICROSCOPY	5.04
5IYA	ELECTRON MICROSCOPY	5.4
8WAK	ELECTRON MICROSCOPY	5.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52655-F1	56.93	0.21

Functional residue map

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

Catalytic / active sites (1): 274–275 (cleavage; by tasp1)

Ligand- & substrate-binding residues (2): 343; 344

Post-translational modifications (5): 2, 280, 281, 316, 321

Mutagenesis-validated functional residues (13):

Position	Phenotype
270	slightly affects cleavage and yields elevated levels of the precursor.
272	abolishes cleavage.
273	abolishes cleavage.
274	abolishes cleavage.
275	abolishes cleavage.
276	does not affect cleavage.
277	does not affect cleavage.
278	significant reduction of cleavage.
280	slightly affects cleavage, yields elevated levels of the precursor. eliminates phosphorylation; when associated with a-2
281	eliminates phosphorylation; when associated with a-280; a-316 and a-321.
282	slightly affects cleavage and yields elevated levels of the precursor.
316	strongly reduces phosphorylation; when associated with a-321. eliminates phosphorylation; when associated with a-280; a-
321	strongly reduces phosphorylation; when associated with a-316. eliminates phosphorylation; when associated with a-280; a-

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-167161	HIV Transcription Initiation
R-HSA-167162	RNA Polymerase II HIV Promoter Escape
R-HSA-167172	Transcription of the HIV genome
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-6807505	RNA polymerase II transcribes snRNA genes
R-HSA-73776	RNA Polymerase II Promoter Escape
R-HSA-73779	RNA Polymerase II Transcription Pre-Initiation And Promoter Opening
R-HSA-75953	RNA Polymerase II Transcription Initiation
R-HSA-76042	RNA Polymerase II Transcription Initiation And Promoter Clearance
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-162582	Signal Transduction
R-HSA-162587	HIV Life Cycle
R-HSA-162599	Late Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-1643685	Disease
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8939211	ESR-mediated signaling
R-HSA-9006931	Signaling by Nuclear Receptors
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 361 (showing top): AHRARNT_01, HNF3ALPHA_Q6, TGCGCANK_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, CGGAARNGGCNG_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, IVANOVA_HEMATOPOIESIS_MATURE_CELL, CREBP1_Q2, RACCACAR_AML_Q6, BROWNE_HCMV_INFECTION_12HR_UP, USF_C, CREB_Q4, REACTOME_HIV_INFECTION, YY1_02, USF_01

GO Biological Process (5): transcription by RNA polymerase II (GO:0006366), positive regulation of transcription by RNA polymerase II (GO:0045944), RNA polymerase II preinitiation complex assembly (GO:0051123), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), transcription initiation at RNA polymerase II promoter (GO:0006367)

GO Molecular Function (8): RNA polymerase II core promoter sequence-specific DNA binding (GO:0000979), RNA polymerase II general transcription initiation factor binding (GO:0001091), DNA binding (GO:0003677), RNA polymerase II general transcription initiation factor activity (GO:0016251), TBP-class protein binding (GO:0017025), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription factor TFIID complex (GO:0005669), transcription factor TFIIA complex (GO:0005672), cytosol (GO:0005829), transcription preinitiation complex (GO:0097550), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
RNA Polymerase II Transcription	4
Transcription of the HIV genome	2
RNA Polymerase II Transcription Initiation And Promoter Clearance	2
Late Phase of HIV Life Cycle	1
ESR-mediated signaling	1
HIV Infection	1
HIV Life Cycle	1
Viral Infection Pathways	1
Disease	1
Gene expression (Transcription)	1
Signaling by Nuclear Receptors	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
cellular anatomical structure	3
transcription initiation at RNA polymerase II promoter	2
general transcription initiation factor binding	2
RNA polymerase II, holoenzyme	2
RNA polymerase II transcription regulator complex	2
DNA-templated transcription	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
transcription preinitiation complex assembly	1
positive regulation of transcription by RNA polymerase II	1
regulation of transcription initiation by RNA polymerase II	1
positive regulation of DNA-templated transcription initiation	1
DNA-templated transcription initiation	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
core promoter sequence-specific DNA binding	1
RNA polymerase II complex binding	1
nucleic acid binding	1
general transcription initiation factor activity	1
protein dimerization activity	1
DNA-binding transcription factor binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
protein-DNA complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1418 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GTF2A1	GTF2A2	P52657	962
GTF2A1	TBP	P20226	861
GTF2A1	GTF2B	Q00403	861
GTF2A1	TBPL1	P62380	858
GTF2A1	STON1	Q9Y6Q2	847
GTF2A1	STON2	Q8WXE9	817
GTF2A1	MED1	Q15648	781
GTF2A1	POLR2A	P24928	772
GTF2A1	ERCC3	P19447	766
GTF2A1	GTF2E1	P29083	732
GTF2A1	MED27	Q6P2C8	717
GTF2A1	MED26	O95402	668
GTF2A1	MED7	O43513	649
GTF2A1	MED23	Q9ULK4	648
GTF2A1	MED14	O60244	597

IntAct

75 interactions, top by confidence:

A	B	Type	Score
GTF2A1	GTF2A2	psi-mi:“MI:0915”(physical association)	0.940
GTF2A2	GTF2A1	psi-mi:“MI:0915”(physical association)	0.940
GTF2A1	GTF2A2	psi-mi:“MI:0407”(direct interaction)	0.940
GTF2A1	TBPL1	psi-mi:“MI:0915”(physical association)	0.850
TBPL1	GTF2A1	psi-mi:“MI:0915”(physical association)	0.850
POLR2E	POLR2D	psi-mi:“MI:0915”(physical association)	0.790
TBP	GTF2A1	psi-mi:“MI:0915”(physical association)	0.740
GTF2A1	TBP	psi-mi:“MI:0914”(association)	0.740
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
GTF2A1	NFYA	psi-mi:“MI:0915”(physical association)	0.560
NFYA	GTF2A1	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	PRR20D	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	SP4	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	BIRC7	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	PSMC6	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1		psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	ERN1	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	FKBP1A	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	HRAS	psi-mi:“MI:0915”(physical association)	0.560
GTF2A1	PMP22	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (128): GTF2A1 (Affinity Capture-MS), GTF2A2 (Two-hybrid), NFYA (Two-hybrid), GTF2A1 (Affinity Capture-RNA), GTF2A1 (Affinity Capture-Western), TBP (Affinity Capture-Western), Tbp (Affinity Capture-Western), GTF2A1 (Affinity Capture-MS), C17orf62 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), GTF2A2 (Affinity Capture-MS), TBPL1 (Affinity Capture-MS), PTCD2 (Affinity Capture-MS), TBP (Affinity Capture-MS), GTF2A2 (Co-fractionation)

ESM2 similar proteins: A1Z9E2, A4QNP0, B0R0I6, B5DE69, F1MH24, F1SPM8, O08949, O94842, P0C1X8, P0CF24, P27699, P34333, P52655, P79145, Q01167, Q02086, Q03061, Q08CM4, Q09XV5, Q0IHV2, Q0P5K4, Q1LZH5, Q2M2I8, Q3TUF7, Q3UCQ1, Q3UHJ0, Q571G4, Q58NQ4, Q5E9U0, Q5QL03, Q5R6A9, Q5RBN8, Q5RCU0, Q641Z1, Q6DJL0, Q6IRR0, Q6MZP7, Q7ZUV7, Q7ZX03, Q86NP2

Diamond homologs: O08949, P32773, P52654, P52655, Q54G80, Q5RCU0, Q8R4I4, Q8SW23, Q99PM3, Q9UNN4, Q9USU9

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
TAF1	“up-regulates activity”	GTF2A1	phosphorylation
TAF1	up-regulates	GTF2A1	phosphorylation
GTF2A1	“form complex”	TFIIA	binding
CSNK2A1	“up-regulates activity”	GTF2A1	phosphorylation
CSNK2A2	“up-regulates activity”	GTF2A1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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
HIV Transcription Initiation	6	53.8×	6e-08
RNA Polymerase II HIV Promoter Escape	6	53.8×	6e-08
RNA Polymerase II Promoter Escape	6	53.8×	6e-08
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	6	53.8×	6e-08
RNA Polymerase II Transcription Initiation	6	53.8×	6e-08
RNA Polymerase II Transcription Initiation And Promoter Clearance	6	53.8×	6e-08
Transcription of the HIV genome	6	39.9×	3e-07
Late Phase of HIV Life Cycle	5	32.3×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
transcription initiation at RNA polymerase II promoter	5	55.1×	4e-06
transcription by RNA polymerase II	8	16.6×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2181 predictions. Top by Δscore:

Variant	Effect	Δscore
14:81185526:CTTA:C	donor_loss	1.0000
14:81185527:TTACC:T	donor_loss	1.0000
14:81185528:TACC:T	donor_loss	1.0000
14:81185529:A:AC	donor_gain	1.0000
14:81185529:A:AT	donor_loss	1.0000
14:81185530:C:A	donor_loss	1.0000
14:81185530:C:CC	donor_gain	1.0000
14:81185616:GGCTC:G	acceptor_gain	1.0000
14:81185618:CTC:C	acceptor_gain	1.0000
14:81185619:TC:T	acceptor_gain	1.0000
14:81185620:CC:C	acceptor_gain	1.0000
14:81185621:C:CC	acceptor_gain	1.0000
14:81185627:A:AC	acceptor_gain	1.0000
14:81185627:A:C	acceptor_gain	1.0000
14:81192512:AACTT:A	donor_loss	1.0000
14:81192513:ACTTA:A	donor_loss	1.0000
14:81192514:CTT:C	donor_loss	1.0000
14:81192515:TTA:T	donor_loss	1.0000
14:81192516:TA:T	donor_loss	1.0000
14:81192517:A:AC	donor_gain	1.0000
14:81192517:A:AT	donor_loss	1.0000
14:81192517:ACTT:A	donor_gain	1.0000
14:81192518:C:CG	donor_gain	1.0000
14:81192518:CT:C	donor_gain	1.0000
14:81192518:CTT:C	donor_gain	1.0000
14:81192518:CTTC:C	donor_gain	1.0000
14:81192520:T:TA	donor_gain	1.0000
14:81192836:GCAC:G	acceptor_gain	1.0000
14:81192837:CAC:C	acceptor_gain	1.0000
14:81192837:CACC:C	acceptor_gain	1.0000

AlphaMissense

2484 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:81180226:C:A	W376C	1.000
14:81180226:C:G	W376C	1.000
14:81180228:A:G	W376R	1.000
14:81180228:A:T	W376R	1.000
14:81180234:C:G	A374P	1.000
14:81180239:C:T	G372E	1.000
14:81180240:C:G	G372R	1.000
14:81180240:C:T	G372R	1.000
14:81180245:G:T	A370D	1.000
14:81180246:C:G	A370P	1.000
14:81180248:T:A	K369I	1.000
14:81180253:A:C	F367L	1.000
14:81180253:A:T	F367L	1.000
14:81180254:A:C	F367C	1.000
14:81180254:A:G	F367S	1.000
14:81180255:A:G	F367L	1.000
14:81180275:A:G	L360P	1.000
14:81180281:A:T	M358K	1.000
14:81180287:C:A	G356V	1.000
14:81180287:C:T	G356D	1.000
14:81180288:C:A	G356C	1.000
14:81180288:C:G	G356R	1.000
14:81180288:C:T	G356S	1.000
14:81180292:C:A	K354N	1.000
14:81180292:C:G	K354N	1.000
14:81180294:T:C	K354E	1.000
14:81180296:A:G	L353P	1.000
14:81180301:A:C	F351L	1.000
14:81180301:A:T	F351L	1.000
14:81180302:A:G	F351S	1.000

dbSNP variants (sampled 300 via entrez): RS1000042907 (14:81221684 C>G), RS1000095806 (14:81177870 C>T), RS1000116247 (14:81194398 A>C,G), RS1000164876 (14:81179548 A>G), RS1000367664 (14:81223205 G>A), RS1000449937 (14:81193217 A>C), RS1000477944 (14:81175914 C>T), RS1000488463 (14:81190753 G>A), RS1000589701 (14:81183173 T>C), RS1000593436 (14:81177558 G>A), RS1000773384 (14:81189173 T>C), RS1000775489 (14:81180753 TA>T,TAA), RS1000793252 (14:81187584 G>T), RS1000839249 (14:81190378 G>A), RS1000903846 (14:81195249 C>T)

Disease associations

OMIM: gene MIM:600520 | disease phenotypes: MIM:220200

GenCC curated gene-disease

Mondo (1): Dandy-Walker syndrome (MONDO:0009072)

Orphanet (1): Isolated Dandy-Walker malformation (Orphanet:217)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003542_76	Night sleep phenotypes	4.000000e-06
GCST010241_52	Apolipoprotein A1 levels	7.000000e-15
GCST010242_337	HDL cholesterol levels	3.000000e-13
GCST010653_82	Thyroid stimulating hormone levels	7.000000e-22
GCST010653_83	Thyroid stimulating hormone levels	1.000000e-12
GCST90002398_223	Neutrophil count	8.000000e-16
GCST90002407_578	White blood cell count	3.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004833	neutrophil count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4832 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

22 measured of 22 human assays (22 total across all organisms); most potent 22 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-pyridin-4-ylbutanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	20 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-piperidin-4-ylbutanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	90 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-oxidopyridin-1-ium-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	120 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-piperidin-4-ylpentanamide	KI	300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-(1-oxidopyridin-1-ium-4-yl)pentanamide	KI	400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 4-[(4R)-4-(benzylsulfonylamino)-5-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-5-oxopentyl]piperidine-1-carboxylate	KI	400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
BDBM108100	KI	750 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-pyridin-4-ylpentanamide	KI	850 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-phenylpentanamide	KI	1100 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(2-methoxyacetyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1600 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-2-phenylacetyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1600 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]-N-methylpiperidine-1-carboxamide	KI	1700 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-4-(1-acetylpiperidin-4-yl)-2-(benzylsulfonylamino)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1900 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]piperidine-1-carboxylate	KI	2000 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-butanoylpiperidin-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2200 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(cyclopropanecarbonyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-propanoylpiperidin-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	KI	2400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-(tetrazol-1-yl)pentanamide	KI	2400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]-N,N-dimethylpiperidine-1-carboxamide	KI	2500 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(2-methylpropanoyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	3200 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoate	KI	5900 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use

ChEMBL bioactivities

20 potent at pChembl≥5 of 24 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.62	Ki	240	nM	CHEMBL3660186
6.10	Ki	800	nM	CHEMBL3660173
6.04	Ki	920	nM	CHEMBL3660190
5.92	Ki	1200	nM	CHEMBL3660191
5.77	Ki	1700	nM	CHEMBL3660187
5.44	Ki	3600	nM	CHEMBL3660189
5.42	Ki	3800	nM	CHEMBL3660176
5.41	Ki	3900	nM	CHEMBL3660179
5.38	Ki	4200	nM	CHEMBL3660177
5.36	Ki	4400	nM	CHEMBL3660171
5.35	Ki	4500	nM	CHEMBL3660178
5.33	Ki	4700	nM	CHEMBL3660192
5.32	Ki	4800	nM	CHEMBL3660181
5.31	Ki	4900	nM	CHEMBL3660184
5.26	Ki	5500	nM	CHEMBL3660182
5.25	Ki	5600	nM	CHEMBL3660175
5.10	Ki	8000	nM	CHEMBL3660172
5.07	Ki	8500	nM	CHEMBL3660174
5.05	Ki	9000	nM	CHEMBL3660188

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	decreases expression	2
aristolochic acid I	decreases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
sodium arsenate	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	increases expression, affects cotreatment	1
Arsenic Trioxide	increases sumoylation	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Gemcitabine	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Butyrates	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Folic Acid	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression, increases abundance	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3705624	Binding	Inhibition Assay: Inhibition of human FIIa was determined by the method described in [0092]-[0098] using human alpha-thrombin from Enzyme Research Laboratories at 0.1 NIH U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 2 mM, 1 mM, and 0.	Trypsin-like serine protease inhibitors, and their preparation and use

Clinical trials (associated diseases)

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