GTF2H1

Summary

GTF2H1 (general transcription factor IIH subunit 1, HGNC:4655) is a protein-coding gene on chromosome 11p15.1, encoding General transcription factor IIH subunit 1 (P32780). Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. It is a selective cancer dependency (DepMap: 85.3% of cell lines).

Enables nuclear thyroid hormone receptor binding activity. Involved in positive regulation of DNA-templated transcription and transcription initiation at RNA polymerase II promoter. Located in nucleoplasm. Part of transcription factor TFIIH core complex and transcription factor TFIIH holo complex.

Source: NCBI Gene 2965 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 85 total
• Phenotypes (HPO): 1
• Cancer dependency (DepMap): dependent in 85.3% of screened cell lines
• MANE Select transcript: NM_005316

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4655
Approved symbol	GTF2H1
Name	general transcription factor IIH subunit 1
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	BTF2, P62, TFIIH
Ensembl gene	ENSG00000110768
Ensembl biotype	protein_coding
OMIM	189972
Entrez	2965

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 15 protein_coding, 9 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000265963, ENST00000418116, ENST00000453096, ENST00000524753, ENST00000525831, ENST00000526282, ENST00000526461, ENST00000526630, ENST00000528427, ENST00000530496, ENST00000531757, ENST00000532227, ENST00000534213, ENST00000534641, ENST00000543932, ENST00000607664, ENST00000868128, ENST00000868129, ENST00000868130, ENST00000868131, ENST00000928992, ENST00000928993, ENST00000951596, ENST00000951597, ENST00000951598, ENST00000951599

RefSeq mRNA: 2 — MANE Select: NM_005316 NM_001142307, NM_005316

CCDS: CCDS7838

Canonical transcript exons

ENST00000265963 — 15 exons

Exon	Start	End
ENSE00001106704	18365783	18367045
ENSE00001313403	18322567	18322740
ENSE00001763947	18360615	18360707
ENSE00003464709	18333060	18333228
ENSE00003468042	18341261	18341410
ENSE00003476408	18339564	18339657
ENSE00003508552	18351881	18351969
ENSE00003545948	18347588	18347715
ENSE00003559492	18347832	18347919
ENSE00003607586	18358525	18358640
ENSE00003639307	18357952	18358042
ENSE00003662049	18338109	18338274
ENSE00003674066	18335754	18335946
ENSE00003683667	18352329	18352446
ENSE00003686824	18341528	18341607

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 94.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.1054 / max 536.7557, expressed in 1825 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113321	27.0063	1813
113319	7.5646	1756
113320	7.1768	1741
113322	1.3576	691

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	94.61	gold quality
adrenal tissue	UBERON:0018303	94.45	gold quality
corpus callosum	UBERON:0002336	93.38	gold quality
endometrium	UBERON:0001295	92.32	gold quality
tonsil	UBERON:0002372	92.26	gold quality
right testis	UBERON:0004534	91.51	gold quality
testis	UBERON:0000473	91.48	gold quality
left testis	UBERON:0004533	91.48	gold quality
monocyte	CL:0000576	91.43	gold quality
islet of Langerhans	UBERON:0000006	91.38	gold quality
leukocyte	CL:0000738	91.28	gold quality
smooth muscle tissue	UBERON:0001135	91.23	gold quality
gall bladder	UBERON:0002110	91.01	gold quality
skin of leg	UBERON:0001511	90.91	gold quality
peripheral nervous system	UBERON:0000010	90.84	gold quality
nerve	UBERON:0001021	90.84	gold quality
tibial nerve	UBERON:0001323	90.84	gold quality
zone of skin	UBERON:0000014	90.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.75	gold quality
skin of abdomen	UBERON:0001416	90.56	gold quality
lymph node	UBERON:0000029	90.54	gold quality
pancreas	UBERON:0001264	90.46	gold quality
left ovary	UBERON:0002119	90.45	gold quality
ovary	UBERON:0000992	90.44	gold quality
thoracic mammary gland	UBERON:0005200	90.43	gold quality
mammary gland	UBERON:0001911	90.42	gold quality
minor salivary gland	UBERON:0001830	90.39	gold quality
uterus	UBERON:0000995	90.36	gold quality
tibial artery	UBERON:0007610	90.24	gold quality
popliteal artery	UBERON:0002250	90.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

98 targeting GTF2H1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 85.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• transcription factor b3, previously identified as a component of the transcription factor IIH core complex, is shown instead to be transcription factor b4 (PMID:14500720)
• p62 subunit of TFIIH interacts with TRbeta in a ligand-dependent manner. (PMID:15625236)
• The pleckstrin homology domain from the 62 kDa subunit Tfb1 (residues 1-108) of TFIIH is sufficient for binding to the activation domain of herpes simplex virus protein VP16. (PMID:15909982)
• GTF2H1 polymorphisms/haplotypes may contribute to genetic susceptibility to lung cancer. (PMID:18692935)
• cdk1 phosphorylates p62 in vitro and in vivo at T269 and S272, which is necessary for the maintenance of appropriate cyclin B1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. (PMID:20974803)
• These data suggest that the RVFV NSs protein is able to interact with the TFIIH subunit p62 inside infected cells and promotes its degradation, which can occur directly in the nucleus. (PMID:21543505)
• Virulence factor NSs of rift valley fever virus recruits the FBXO3 to degrade subunit p62 of general transcription factor TFIIH. (PMID:24403578)
• The N-terminal highly acidic region of TFIIEalpha interacts with the pleckstrin homology domain of TFIIH and adopts an extended stringlike structure on the positive groove of the pleckstrin homology domain with two hydrophobic amino acids, Phe387 and Val390, inserting into two shallow hydrophobic pockets of the pleckstrin homology domain. (PMID:27602723)
• Here, the authors show that an acidic region of DP1, whose function has remained elusive, binds to the plekstrin homology (PH) domain of the p62 subunit of TFIIH that contributes to transcriptional activation. (PMID:27825926)
• Data suggest that a common TFIIH subunit p62 recruitment mechanism is shared by UV-stimulated scaffold protein A (UVSSA) in transcription-coupled repair (TCR) and xeroderma pigmentosum, complementation group C protein (XPC) in global genome repair (GGR). (PMID:29069470)
• The sensitivity of SWI/SNF-deficient cells to DNA damage induced by UV irradiation and cisplatin treatment depends on GTF2H1 levels. (PMID:30287812)
• GTF2H1 is a direct transcriptional target of MITF. (PMID:30651597)
• The results unveil a tight connection between TFIIH and KAT2A that controls higher-order chromatin structure and gene expression and provide new insights into transcriptional dysregulation in a cancer-prone DNA repair-deficient disorder, Xeroderma Pigmentosum B-Cockayne Syndrome. (PMID:30894545)
• The TFIIH subunits p44/p62 act as a damage sensor during nucleotide excision repair. (PMID:33166411)
• Structural and dynamical insights into the PH domain of p62 in human TFIIH. (PMID:33211877)
• Three human RNA polymerases interact with TFIIH via a common RPB6 subunit. (PMID:34268577)
• Impact of GTF2H1 and RAD54L2 polymorphisms on the risk of lung cancer in the Chinese Han population. (PMID:36384536)
• Structural characterization of transcription-coupled repair protein UVSSA and its interaction with TFIIH protein. (PMID:37442507)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gtf2h1	ENSDARG00000026701
mus_musculus	Gtf2h1	ENSMUSG00000006599
rattus_norvegicus	Gtf2h1	ENSRNOG00000012360
drosophila_melanogaster	Tfb1	FBGN0033929
caenorhabditis_elegans		WBGENE00019821

Protein

Protein identifiers

General transcription factor IIH subunit 1 — P32780 (reviewed: P32780)

Alternative names: Basic transcription factor 2 62 kDa subunit, General transcription factor IIH polypeptide 1, TFIIH basal transcription factor complex p62 subunit

All UniProt accessions (4): P32780, A0A384MTQ8, E9PI26, E9PL58

UniProt curated annotations — full annotation on UniProt →

Function. Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.

Subunit / interactions. Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. Interacts with PUF60. (Microbial infection) Interacts with Rift valley fever virus NSs (via OmegaXaV motif); the interaction leads to TFIIH complex proteasomal degradation.

Subcellular location. Nucleus.

Post-translational modifications. (Microbial infection) Upon Rift valley fever virus infection, interacts with NSs leading to ubiquitination by the NSs-FBXO3 E3 ligase and proteasome-dependent degradation.

Similarity. Belongs to the TFB1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P32780-1	1	yes
P32780-2	2

RefSeq proteins (2): NP_001135779, NP_005307* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005607	BSD_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013876	TFIIH_BTF_p62_N	Domain
IPR027079	Tfb1/GTF2H1	Family
IPR035925	BSD_dom_sf	Homologous_superfamily

Pfam: PF03909, PF08567

UniProt features (50 total): strand 17, helix 14, turn 5, sequence variant 3, modified residue 3, domain 2, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

52 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
28JM	ELECTRON MICROSCOPY	3.29
7EGB	ELECTRON MICROSCOPY	3.3
8EBU	ELECTRON MICROSCOPY	3.3
9PD3	ELECTRON MICROSCOPY	3.3
28JS	ELECTRON MICROSCOPY	3.32
9PD4	ELECTRON MICROSCOPY	3.4
7AD8	ELECTRON MICROSCOPY	3.5
9XYU	ELECTRON MICROSCOPY	3.5
28KE	ELECTRON MICROSCOPY	3.6
8EBX	ELECTRON MICROSCOPY	3.6
8EBY	ELECTRON MICROSCOPY	3.6
6NMI	ELECTRON MICROSCOPY	3.7
7EGC	ELECTRON MICROSCOPY	3.9
7NVX	ELECTRON MICROSCOPY	3.9
8EBT	ELECTRON MICROSCOPY	3.9
28JV	ELECTRON MICROSCOPY	3.91
8BVW	ELECTRON MICROSCOPY	4
8EBS	ELECTRON MICROSCOPY	4
7ENA	ELECTRON MICROSCOPY	4.07
8BYQ	ELECTRON MICROSCOPY	4.1
7ENC	ELECTRON MICROSCOPY	4.13
8GXS	ELECTRON MICROSCOPY	4.16
7NVW	ELECTRON MICROSCOPY	4.3
9PCP	ELECTRON MICROSCOPY	4.3
6O9M	ELECTRON MICROSCOPY	4.4
7NVR	ELECTRON MICROSCOPY	4.5
7LBM	ELECTRON MICROSCOPY	4.8
8GXQ	ELECTRON MICROSCOPY	5.04
8WAK	ELECTRON MICROSCOPY	5.47
8EBW	ELECTRON MICROSCOPY	5.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P32780-F1	74.54	0.04

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 (3): 240, 339, 357

Function

Pathways and Gene Ontology

Reactome pathways

48 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-113418	Formation of the Early Elongation Complex
R-HSA-167152	Formation of HIV elongation complex in the absence of HIV Tat
R-HSA-167158	Formation of the HIV-1 Early Elongation Complex
R-HSA-167160	RNA Pol II CTD phosphorylation and interaction with CE during HIV infection
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-167200	Formation of HIV-1 elongation complex containing HIV-1 Tat
R-HSA-167246	Tat-mediated elongation of the HIV-1 transcript
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-5696395	Formation of Incision Complex in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-72086	mRNA Capping
R-HSA-73762	RNA Polymerase I Transcription Initiation
R-HSA-73772	RNA Polymerase I Promoter Escape
R-HSA-73776	RNA Polymerase II Promoter Escape
R-HSA-73779	RNA Polymerase II Transcription Pre-Initiation And Promoter Opening
R-HSA-73863	RNA Polymerase I Transcription Termination
R-HSA-75953	RNA Polymerase II Transcription Initiation
R-HSA-75955	RNA Polymerase II Transcription Elongation
R-HSA-76042	RNA Polymerase II Transcription Initiation And Promoter Clearance
R-HSA-77075	RNA Pol II CTD phosphorylation and interaction with CE
R-HSA-162587	HIV Life Cycle

MSigDB gene sets: 284 (showing top): REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_RNA_POLYMERASE_I_TRANSCRIPTION_INITIATION, MAZ_Q6, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, KAUFFMANN_DNA_REPAIR_GENES, ACTGCAG_MIR173P, USF_C, MORF_PSMC2, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NUCLEOTIDE_EXCISION_REPAIR, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, REACTOME_HIV_INFECTION, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (10): regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), DNA repair (GO:0006281), nucleotide-excision repair (GO:0006289), transcription by RNA polymerase I (GO:0006360), transcription by RNA polymerase II (GO:0006366), transcription initiation at RNA polymerase II promoter (GO:0006367), hormone-mediated signaling pathway (GO:0009755), positive regulation of DNA-templated transcription (GO:0045893), DNA-templated transcription (GO:0006351), DNA damage response (GO:0006974)

GO Molecular Function (3): chromatin binding (GO:0003682), nuclear thyroid hormone receptor binding (GO:0046966), protein binding (GO:0005515)

GO Cellular Component (4): transcription factor TFIIH core complex (GO:0000439), nucleoplasm (GO:0005654), transcription factor TFIIH holo complex (GO:0005675), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Transcription of the HIV genome	4
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	3
RNA Polymerase II Transcription Elongation	2
HIV Transcription Elongation	2
Global Genome Nucleotide Excision Repair (GG-NER)	2
Late Phase of HIV Life Cycle	1
Tat-mediated elongation of the HIV-1 transcript	1
Negative epigenetic regulation of rRNA expression	1
RNA Polymerase II Transcription	1
Nucleotide Excision Repair	1
Transcriptional Regulation by TP53	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	3
binding	2
RNA polymerase II transcription regulator complex	2
cyclin-dependent protein serine/threonine kinase activity	1
regulation of protein serine/threonine kinase activity	1
DNA metabolic process	1
DNA damage response	1
DNA repair	1
DNA-templated transcription initiation	1
transcription by RNA polymerase II	1
signal transduction	1
cellular response to hormone stimulus	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
gene expression	1
RNA biosynthetic process	1
cellular response to stress	1
nuclear receptor binding	1
nuclear lumen	1
cellular anatomical structure	1
transcription factor TFIIH core complex	1
RNA polymerase II, holoenzyme	1
nuclear cyclin-dependent protein kinase holoenzyme complex	1
carboxy-terminal domain protein kinase complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1559 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GTF2H1	GTF2H4	Q92759	999
GTF2H1	GTF2H2	Q13888	999
GTF2H1	ERCC3	P19447	998
GTF2H1	ERCC2	P18074	997
GTF2H1	GTF2H3	Q13889	997
GTF2H1	GTF2H5	Q6ZYL4	996
GTF2H1	CCNH	P51946	964
GTF2H1	CDK7	P50613	921
GTF2H1	MNAT1	P51948	881
GTF2H1	GTF2E1	P29083	828
GTF2H1	TBP	P20226	803
GTF2H1	XPA	P23025	795
GTF2H1	IMMT	Q16891	780
GTF2H1	ADAT2	Q7Z6V5	772
GTF2H1	GTF2H2C	Q6P1K8	770

IntAct

135 interactions, top by confidence:

A	B	Type	Score
CCNH	ERCC3	psi-mi:“MI:0914”(association)	0.850
GTF2H1	CDK7	psi-mi:“MI:0915”(physical association)	0.820
ERCC3	GTF2H1	psi-mi:“MI:0914”(association)	0.790
GTF2E1	GTF2H1	psi-mi:“MI:0407”(direct interaction)	0.790
GTF2E1	GTF2H1	psi-mi:“MI:0915”(physical association)	0.790
GTF2H1	GTF2E1	psi-mi:“MI:0407”(direct interaction)	0.790
CCNH	ERCC2	psi-mi:“MI:0915”(physical association)	0.750
GTF2H3	GTF2H1	psi-mi:“MI:0914”(association)	0.740
CETN2	SFI1	psi-mi:“MI:0914”(association)	0.740
GTF2H5	GTF2H1	psi-mi:“MI:0914”(association)	0.730
TP53	GTF2H1	psi-mi:“MI:0407”(direct interaction)	0.720

BioGRID (205): GTF2H1 (Affinity Capture-Western), GTF2H1 (Affinity Capture-MS), GTF2H1 (Affinity Capture-MS), GTF2H1 (Co-fractionation), GTF2H1 (Co-fractionation), GTF2H2C (Co-fractionation), GTF2H2 (Co-fractionation), GTF2H2C_2 (Co-fractionation), GTF2H4 (Co-fractionation), POLR2A (Biochemical Activity), GTF2H1 (Affinity Capture-MS), GTF2H1 (Affinity Capture-MS), GTF2H1 (Affinity Capture-MS), GTF2H1 (Affinity Capture-MS), GTF2H1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4I9, A5D796, A5PJZ5, A7S2N8, A9ULY7, B0F9L4, B2GV24, F4HQ84, F4IDS7, O60308, O75694, O75717, O94874, P32780, P37199, P59328, Q14CX7, Q1RMS6, Q28HX4, Q4R367, Q5R822, Q5RBW9, Q5ZL91, Q5ZMG1, Q66HC5, Q6DDM4, Q6NX12, Q6P3X3, Q6PGY6, Q7TQK1, Q7ZU29, Q7ZX96, Q8BGQ1, Q8BJ71, Q8BWZ3, Q8CCJ3, Q8JGR7, Q8N1F7, Q8R3N6, Q8WVM7

Diamond homologs: O13745, P32776, P32780, Q55FP1, Q960E8, Q9DBA9, Q9M322, Q9P5N7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GTF2H1	“form complex”	TFIIH	binding
GTF2H1	“down-regulates quantity by destabilization”	E2F1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	11	83.1×	1e-17
RNA Pol II CTD phosphorylation and interaction with CE	11	83.1×	1e-17
mRNA Capping	11	77.5×	2e-17
Formation of the Early Elongation Complex	11	68.4×	5e-17
Formation of the HIV-1 Early Elongation Complex	11	68.4×	5e-17
HIV Transcription Elongation	10	62.2×	4e-15
Formation of Incision Complex in GG-NER	13	61.1×	3e-18
Global Genome Nucleotide Excision Repair (GG-NER)	7	59.2×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
nucleotide-excision repair	13	67.3×	2e-18
transcription initiation at RNA polymerase II promoter	9	45.5×	8e-11
transcription by RNA polymerase II	10	9.5×	2e-05
DNA repair	9	7.8×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2161 predictions. Top by Δscore:

Variant	Effect	Δscore
11:18333058:A:AG	acceptor_gain	1.0000
11:18333059:G:GG	acceptor_gain	1.0000
11:18333059:GC:G	acceptor_gain	1.0000
11:18333059:GCAC:G	acceptor_gain	1.0000
11:18333059:GCACC:G	acceptor_gain	1.0000
11:18333185:C:T	donor_gain	1.0000
11:18333226:AAT:A	donor_gain	1.0000
11:18333227:AT:A	donor_gain	1.0000
11:18333227:ATGT:A	donor_loss	1.0000
11:18333228:TGT:T	donor_loss	1.0000
11:18333229:G:A	donor_loss	1.0000
11:18333229:G:GG	donor_gain	1.0000
11:18335752:A:AG	acceptor_gain	1.0000
11:18335753:G:GG	acceptor_gain	1.0000
11:18335915:A:T	donor_gain	1.0000
11:18335933:G:GT	donor_gain	1.0000
11:18335942:AACAG:A	donor_loss	1.0000
11:18335943:ACAGG:A	donor_loss	1.0000
11:18335944:CAGG:C	donor_loss	1.0000
11:18335945:AGGT:A	donor_loss	1.0000
11:18335946:GGTGG:G	donor_loss	1.0000
11:18335948:T:A	donor_loss	1.0000
11:18338107:A:AG	acceptor_gain	1.0000
11:18338108:G:GG	acceptor_gain	1.0000
11:18338248:G:GT	donor_gain	1.0000
11:18338272:CTGG:C	donor_loss	1.0000
11:18338273:TGGT:T	donor_loss	1.0000
11:18338275:G:GG	donor_gain	1.0000
11:18338275:GTAT:G	donor_loss	1.0000
11:18341256:CACA:C	acceptor_loss	1.0000

AlphaMissense

3642 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:18333138:G:A	G22R	1.000
11:18333138:G:C	G22R	1.000
11:18333139:G:A	G22E	1.000
11:18333139:G:T	G22V	1.000
11:18333145:T:C	L24P	1.000
11:18333151:T:C	L26P	1.000
11:18333169:C:A	A32D	1.000
11:18333171:T:A	W33R	1.000
11:18333171:T:C	W33R	1.000
11:18333172:G:C	W33S	1.000
11:18333213:T:G	Y47D	1.000
11:18333223:T:A	I50N	1.000
11:18335765:A:C	S56R	1.000
11:18335767:T:A	S56R	1.000
11:18335767:T:G	S56R	1.000
11:18335793:T:C	L65P	1.000
11:18335799:T:C	L67P	1.000
11:18335829:T:C	F77S	1.000
11:18335834:T:C	F79L	1.000
11:18335835:T:C	F79S	1.000
11:18335836:T:A	F79L	1.000
11:18335836:T:G	F79L	1.000
11:18335865:G:C	R89P	1.000
11:18335883:T:C	L95P	1.000
11:18335886:T:A	L96H	1.000
11:18335886:T:C	L96P	1.000
11:18335895:T:C	L99P	1.000
11:18335906:T:C	F103L	1.000
11:18335908:C:A	F103L	1.000
11:18335908:C:G	F103L	1.000

dbSNP variants (sampled 300 via entrez): RS1000021205 (11:18334869 G>C), RS1000026169 (11:18355224 G>A), RS1000071869 (11:18344489 C>T), RS1000110856 (11:18322076 C>T), RS1000173950 (11:18329520 C>T), RS1000190934 (11:18323166 C>A,T), RS1000234371 (11:18361049 C>T), RS1000253867 (11:18329200 T>C), RS1000265737 (11:18329742 C>T), RS1000313970 (11:18355411 G>A), RS1000346016 (11:18324065 T>G), RS1000365492 (11:18328891 A>T), RS1000432948 (11:18334320 C>T), RS1000455098 (11:18340388 A>G), RS1000515681 (11:18357361 A>G,T)

Disease associations

OMIM: gene MIM:189972 | disease phenotypes: MIM:612933

GenCC curated gene-disease

Mondo (2): glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (MONDO:0013047), oligospermia (MONDO:0001913)

Orphanet (1): Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (Orphanet:284426)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000798	Oligozoospermia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000876_1	Amyloid A serum levels	2.000000e-51
GCST000876_4	Amyloid A serum levels	3.000000e-111
GCST001749_5	Pancreatic cancer	9.000000e-06
GCST004485_47	Survival in pancreatic cancer	5.000000e-06
GCST006249_20	Serum metabolite levels	3.000000e-16
GCST011956_48	Systemic lupus erythematosus	3.000000e-17
GCST012020_422	Serum metabolite levels	6.000000e-40
GCST012020_423	Serum metabolite levels	9.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000638	overall survival

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009845	Oligospermia	C12.100.500.430.508; C12.100.750.700.508; C12.200.294.430.508
C538133	Lactate dehydrogenase deficiency type A (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
geraniol	increases expression	1
trichostatin A	decreases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	decreases expression	1
coumarin	increases phosphorylation	1
aluminum sulfate	decreases expression	1
CPG-oligonucleotide	decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
riccardin D	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Decitabine	affects binding, affects cotreatment, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT05320536	PHASE4	UNKNOWN	A Clinical Study of Gulingji Capsule in the Treatment of Idiopathic Oligospermia, Asthenia, and Teratozoospermia
NCT06260007	PHASE4	RECRUITING	Efficacy and Safety Study of Products Based on Tribulus Terrestris, L. in Men With Oligospermia
NCT00440180	PHASE3	TERMINATED	Aromatase Inhibitors in the Treatment of Male Infertility
NCT01409837	PHASE2	COMPLETED	The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
NCT02234206	PHASE2	COMPLETED	A Clinical Trial to Study the Safety and Efficacy of Chandrakanthi Choornam in Patients With Low Sperm Count
NCT07481370	PHASE2	ENROLLING_BY_INVITATION	Isotretinoin vs hCG for Male Infertility Due to Low or Absent Sperm
NCT05158114	PHASE1	WITHDRAWN	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for Testicular Injury and Oligospermia
NCT07459582	Not specified	RECRUITING	Accuracy of Home Lactate Meter and Accu-chek Glucometer in Patients With Glycogen Storage Disease
NCT02063256	PHASE2/PHASE3	UNKNOWN	7 NUTS Study. Diet Modification and Male Fertility.
NCT06869863	PHASE1/PHASE2	RECRUITING	Study of Tolerability, Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of the Medicinal Product MediReg®
NCT00479960	EARLY_PHASE1	UNKNOWN	A Preliminary Study on Effect of Omega-3 on Human Sperm
NCT06342856	EARLY_PHASE1	UNKNOWN	Evaluation of Treatment With Coenzyme Q10 and L-Carnitine on Semen Parameters in Infertile Men With Idiopathic Oligoasthenoteratospermia
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT01239186	Not specified	COMPLETED	Identification and Characterization of the Methylation Abnormalities on Whole Genome Among Infertile Men
NCT01509482	Not specified	COMPLETED	Insulin Resistance in Idiopathic Oligospermia and Azoospermia
NCT01520584	Not specified	UNKNOWN	Supplement Intake in Infertile Men;the Effect on Sperm Parameters,Fertilization Rate and Embryo Quality
NCT01828710	Not specified	COMPLETED	Myo-inositol on Human Semen Parameters
NCT01856361	Not specified	TERMINATED	Ramipril for the Treatment of Oligospermia
NCT02155179	Not specified	COMPLETED	Sperm Pathology Samples and Morphokinetics
NCT03898752	Not specified	COMPLETED	Is Oxidative Stress in Semen Reduced by Lifestyle Intervention
NCT04349345	Not specified	COMPLETED	Seminal Fluid’s Changes Over 20 Years
NCT04795440	Not specified	COMPLETED	Comparison of ICSI Outcomes in Cycles Using Testicular and Ejaculate Sperm From Couples With High SDF
NCT05506722	Not specified	UNKNOWN	Using of Testes Shocker in Improving the Spermatogenesis and Sperms Activity
NCT05842239	Not specified	RECRUITING	Hyperbaric Oxygen Therapy for Men Suffering From Infertility Due to Oligospermia.
NCT06202469	Not specified	COMPLETED	Creatine and Ubiquinol for Sperm Quality
NCT07357701	Not specified	RECRUITING	Identifying Genome Variants in Non-Obstructive Azoospermia (NOA) or Primary Ovarian Insufficiency (POI)