GTF2H5

Summary

GTF2H5 (general transcription factor IIH subunit 5, HGNC:21157) is a protein-coding gene on chromosome 6q25.3, encoding General transcription factor IIH subunit 5 (Q6ZYL4). 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.

This gene encodes a subunit of transcription/repair factor TFIIH, which functions in gene transcription and DNA repair. This protein stimulates ERCC3/XPB ATPase activity to trigger DNA opening during DNA repair, and is implicated in regulating cellular levels of TFIIH. Mutations in this gene result in trichothiodystrophy, complementation group A.

Source: NCBI Gene 404672 — RefSeq curated summary.

At a glance

• Gene–disease (curated): trichothiodystrophy 3, photosensitive (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 81 total — 8 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 115
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_207118

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21157
Approved symbol	GTF2H5
Name	general transcription factor IIH subunit 5
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ30544, bA120J8.2, TTD-A, TFB5, TFIIH, TTDA
Ensembl gene	ENSG00000272047
Ensembl biotype	protein_coding
OMIM	608780
Entrez	404672

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000607778, ENST00000648328, ENST00000684993, ENST00000689018, ENST00000689383, ENST00000689809, ENST00000691867, ENST00000889637, ENST00000889638, ENST00000889639, ENST00000889640, ENST00000889641, ENST00000920921, ENST00000920922, ENST00000964671

RefSeq mRNA: 1 — MANE Select: NM_207118 NM_207118

CCDS: CCDS5256

Canonical transcript exons

ENST00000607778 — 3 exons

Exon	Start	End
ENSE00001443487	158170470	158170538
ENSE00003696670	158191977	158199344
ENSE00003835014	158168350	158168395

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.6851 / max 439.1878, expressed in 1816 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70828	42.6851	1816

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	97.79	gold quality
superior surface of tongue	UBERON:0007371	97.74	gold quality
saphenous vein	UBERON:0007318	97.73	gold quality
vena cava	UBERON:0004087	97.61	gold quality
pericardium	UBERON:0002407	97.58	gold quality
trigeminal ganglion	UBERON:0001675	97.54	gold quality
pharyngeal mucosa	UBERON:0000355	97.40	gold quality
pons	UBERON:0000988	97.35	gold quality
body of tongue	UBERON:0011876	97.33	gold quality
lateral globus pallidus	UBERON:0002476	97.29	gold quality
inferior vagus X ganglion	UBERON:0005363	97.05	gold quality
tongue	UBERON:0001723	97.04	gold quality
urethra	UBERON:0000057	96.89	gold quality
pylorus	UBERON:0001166	96.87	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.77	gold quality
superior vestibular nucleus	UBERON:0007227	96.74	gold quality
dorsal root ganglion	UBERON:0000044	96.71	gold quality
nipple	UBERON:0002030	96.67	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.58	gold quality
subthalamic nucleus	UBERON:0001906	96.55	gold quality
sperm	CL:0000019	96.48	gold quality
synovial joint	UBERON:0002217	96.43	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.33	gold quality
ventral tegmental area	UBERON:0002691	96.33	gold quality
trachea	UBERON:0003126	96.21	gold quality
male germ cell	CL:0000015	96.09	gold quality
cardia of stomach	UBERON:0001162	96.00	gold quality
substantia nigra pars compacta	UBERON:0001965	95.97	gold quality
bronchial epithelial cell	CL:0002328	95.96	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-81383	yes	168.65
E-ANND-3	yes	10.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

205 targeting GTF2H5, 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-4673	100.00	66.64	1490
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-9983-3P	99.94	71.48	3631

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• p8/TTD-A, the tenth subunit of TFIIH, has a critical role in DNA repair where it triggers DNA opening by stimulating XPB ATPase activity together with the damage recognition factor XPC-hHR23B. (PMID:16427011)
• TTDA is the first Transcription Factor IIH subunit with a primarily nucleotide excision repair-dedicated role in vivo. (PMID:16669699)
• The solution structure of the p8/TTD-A protein, a small alpha/beta protein built around an antiparallel beta-sheet that forms a homodimer with an extended interface, is reported. (PMID:17350038)
• Findings give new insights into the behavior of TTDA within the context of a living cell and thereby shed light on the complex phenotype of TTD-A patients. (PMID:23729738)
• Transcriptional differences found between various TFIIH subunit variants participate in the phenotypic variability observed among xeroderma pigmentosum, XP associated with Cockayne syndrome, and trichothiodystrophy individuals. (PMID:25620205)
• Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization. (PMID:26463438)
• TTDA inhibited apoptosis by regulating the p53-Bax/Bcl2 axis in glioma. (PMID:32540359)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gtf2h5	ENSDARG00000056099
mus_musculus	Gtf2h5	ENSMUSG00000034345
rattus_norvegicus	Gtf2h5	ENSRNOG00000018007
rattus_norvegicus	LOC120103497	ENSRNOG00000052193
drosophila_melanogaster	Tfb5	FBGN0265968
caenorhabditis_elegans		WBGENE00021904

Protein

Protein identifiers

General transcription factor IIH subunit 5 — Q6ZYL4 (reviewed: Q6ZYL4)

Alternative names: General transcription factor IIH polypeptide 5, TFB5 ortholog, TFIIH basal transcription factor complex TTD-A subunit, TFIIH subunit p8

All UniProt accessions (3): A0A3B3ISL4, A0A8I5KQH8, Q6ZYL4

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. Necessary for the stability of the TFIIH complex and for the presence of normal levels of TFIIH in the cell.

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. 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. Cytoplasm.

Disease relevance. Trichothiodystrophy 3, photosensitive (TTD3) [MIM:616395] A form of trichothiodystrophy, an autosomal recessive disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non-photosensitive forms of the disorder. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TFB5 family.

RefSeq proteins (1): NP_997001* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009400	TFIIH_TTDA/Tfb5	Family
IPR035935	TFB5-like_sf	Homologous_superfamily

Pfam: PF06331

UniProt features (11 total): turn 3, strand 3, helix 2, chain 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

53 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1YDL	X-RAY DIFFRACTION	2.3
7NVV	ELECTRON MICROSCOPY	2.9
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
6RO4	ELECTRON MICROSCOPY	3.5
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
5OF4	ELECTRON MICROSCOPY	4.4
6O9M	ELECTRON MICROSCOPY	4.4
7NVR	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZYL4-F1	69.16	0.00

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 (1): 69

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: 444 (showing top): REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_MATURATION_OF_SSU_RRNA, REACTOME_RNA_POLYMERASE_I_TRANSCRIPTION_INITIATION, GOBP_CELLULAR_RESPONSE_TO_GAMMA_RADIATION, KAUFFMANN_DNA_REPAIR_GENES, GOBP_RRNA_TRANSCRIPTION, chr6q25, GOBP_NUCLEOTIDE_EXCISION_REPAIR, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, REACTOME_HIV_INFECTION, GOBP_RIBOSOMAL_SMALL_SUBUNIT_BIOGENESIS, GOBP_MATURATION_OF_SSU_RRNA_FROM_TRICISTRONIC_RRNA_TRANSCRIPT_SSU_RRNA_5_8S_RRNA_LSU_RRNA, KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_UP

GO Biological Process (9): maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) (GO:0000462), nucleotide-excision repair (GO:0006289), nucleotide-excision repair, preincision complex assembly (GO:0006294), transcription elongation by RNA polymerase I (GO:0006362), transcription by RNA polymerase II (GO:0006366), transcription initiation at RNA polymerase II promoter (GO:0006367), cellular response to gamma radiation (GO:0071480), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (7): transcription factor TFIIH core complex (GO:0000439), nucleoplasm (GO:0005654), transcription factor TFIID complex (GO:0005669), transcription factor TFIIH holo complex (GO:0005675), nucleolus (GO:0005730), cytoplasm (GO:0005737), 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
RNA polymerase II transcription regulator complex	3
nuclear lumen	2
cellular anatomical structure	2
RNA polymerase II, holoenzyme	2
maturation of SSU-rRNA	1
DNA repair	1
nucleotide-excision repair	1
protein-DNA complex assembly	1
DNA-templated transcription elongation	1
transcription by RNA polymerase I	1
DNA-templated transcription	1
DNA-templated transcription initiation	1
transcription by RNA polymerase II	1
response to gamma radiation	1
cellular response to ionizing radiation	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
binding	1
transcription factor TFIIH core complex	1
nuclear cyclin-dependent protein kinase holoenzyme complex	1
carboxy-terminal domain protein kinase complex	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1728 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GTF2H5	ERCC3	P19447	999
GTF2H5	ERCC2	P18074	999
GTF2H5	GTF2H1	P32780	996
GTF2H5	GTF2H4	Q92759	995
GTF2H5	GTF2H3	Q13889	981
GTF2H5	GTF2H2	Q13888	945
GTF2H5	CCNH	P51946	935
GTF2H5	CDK7	P50613	862
GTF2H5	RAD23B	P54727	853
GTF2H5	XPA	P23025	814
GTF2H5	MNAT1	P51948	769
GTF2H5	MPLKIP	Q8TAP9	719
GTF2H5	ERCC1	P07992	667
GTF2H5	IMMT	Q16891	635
GTF2H5	ERCC8	Q13216	583

IntAct

59 interactions, top by confidence:

A	B	Type	Score
GTF2H5	GTF2H4	psi-mi:“MI:0915”(physical association)	0.860
GTF2H5	ERCC3	psi-mi:“MI:0915”(physical association)	0.800
GTF2H5	GTF2H2	psi-mi:“MI:0915”(physical association)	0.800
GTF2H5	GTF2H2	psi-mi:“MI:0914”(association)	0.800
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
ERCC2	ERCC3	psi-mi:“MI:0915”(physical association)	0.670
GTF2H5	ERCC2	psi-mi:“MI:0914”(association)	0.650
GTF2H3	ERCC3	psi-mi:“MI:0914”(association)	0.640
GTF2H3	GTF2H2	psi-mi:“MI:0914”(association)	0.640
GTF2H5	AGR2	psi-mi:“MI:0915”(physical association)	0.560
GTF2H5	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
AGR2	GTF2H5	psi-mi:“MI:0915”(physical association)	0.560
GSC2	GTF2H5	psi-mi:“MI:0915”(physical association)	0.560
GTF2H5	NGRN	psi-mi:“MI:0915”(physical association)	0.560
GTF2H5	ANKRD29	psi-mi:“MI:0915”(physical association)	0.560
INCA1	GTF2H5	psi-mi:“MI:0915”(physical association)	0.560
ERCC3	BCR	psi-mi:“MI:0914”(association)	0.530
GTF2H2C	ERCC3	psi-mi:“MI:0914”(association)	0.530
GTF2H5	GTF2H3	psi-mi:“MI:0914”(association)	0.350
CDK7	SEC16A	psi-mi:“MI:0914”(association)	0.350
GTF2H2C	GTF2H2C	psi-mi:“MI:0914”(association)	0.350

BioGRID (68): GTF2H5 (Affinity Capture-RNA), CCNH (Affinity Capture-MS), CDK7 (Affinity Capture-MS), ERCC2 (Affinity Capture-MS), ERCC3 (Affinity Capture-MS), ERCC5 (Affinity Capture-MS), GTF2H1 (Affinity Capture-MS), GTF2H2 (Affinity Capture-MS), GTF2H3 (Affinity Capture-MS), GTF2H4 (Affinity Capture-MS), ITPR1 (Affinity Capture-MS), MNAT1 (Affinity Capture-MS), NUP98 (Affinity Capture-MS), PPP1R2 (Affinity Capture-MS), RNF40 (Affinity Capture-MS)

ESM2 similar proteins: A4J2H0, A5ID02, A5UC58, A9BIE9, B1ILB1, B3SRR4, B7Q1Q9, D5LJN4, O28329, P0CW38, P19740, P26460, P32774, P34642, P41325, P44171, P44198, P52365, P52457, P52536, P52656, P84786, P96643, Q01010, Q03K83, Q06423, Q18LD6, Q25330, Q2EET0, Q2T9Z5, Q37870, Q39236, Q3ZK62, Q4Q1E7, Q4QKH3, Q5QWP6, Q5WVK6, Q5X472, Q5ZUF4, Q65186

Diamond homologs: Q2T9Z5, Q4HYI0, Q4WYX0, Q55CT8, Q5ZKH0, Q6C1B5, Q6NNM0, Q6ZYL4, Q8K2X8, Q8X0V0, Q9N390, P0C0X3, Q3E7C1, Q6BVH4, Q6CTL5, Q6FM86, Q74ZQ0, Q9HDW3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GTF2H5	“form complex”	TFIIH	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 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	9	146.8×	6e-17
RNA Pol II CTD phosphorylation and interaction with CE	9	146.8×	6e-17
mRNA Capping	9	137.0×	7e-17
Formation of the Early Elongation Complex	9	120.9×	2e-16
Formation of the HIV-1 Early Elongation Complex	9	120.9×	2e-16
Global Genome Nucleotide Excision Repair (GG-NER)	6	109.6×	6e-11
RNA Polymerase I Transcription Termination	8	104.4×	3e-14
Formation of Incision Complex in GG-NER	10	101.5×	6e-17

GO biological processes:

GO term	Partners	Fold	FDR
nucleotide-excision repair	9	107.7×	2e-14
transcription initiation at RNA polymerase II promoter	8	93.6×	2e-12
transcription by RNA polymerase II	9	19.8×	3e-08
DNA repair	6	12.0×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	3
Uncertain significance	33
Likely benign	24
Benign	5

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1382813	NM_207118.3(GTF2H5):c.43del (p.Ala15fs)	Pathogenic
2104	NM_207118.3(GTF2H5):c.62T>C (p.Leu21Pro)	Pathogenic
2427776	NC_000006.11:g.(?158591536)(158591590_?)del	Pathogenic
3689291	NM_207118.3(GTF2H5):c.122del (p.Thr41fs)	Pathogenic
4747548	NM_207118.3(GTF2H5):c.1A>G (p.Met1Val)	Pathogenic
975158	NM_207118.3(GTF2H5):c.163G>T (p.Glu55Ter)	Pathogenic
975159	NM_207118.3(GTF2H5):c.49A>T (p.Lys17Ter)	Pathogenic
975160	NM_207118.3(GTF2H5):c.29T>A (p.Ile10Lys)	Pathogenic
1349927	NC_000006.11:g.(?158612989)(158613189_?)del	Likely pathogenic
2136487	NM_207118.3(GTF2H5):c.2T>C (p.Met1Thr)	Likely pathogenic
587425	NM_207118.3(GTF2H5):c.36-2A>G	Likely pathogenic

SpliceAI

392 predictions. Top by Δscore:

Variant	Effect	Δscore
6:158191971:TTACA:T	acceptor_loss	1.0000
6:158191972:TACAG:T	acceptor_loss	1.0000
6:158191973:ACAG:A	acceptor_loss	1.0000
6:158191974:CAGTG:C	acceptor_loss	1.0000
6:158191975:A:AG	acceptor_gain	1.0000
6:158191975:A:AT	acceptor_loss	1.0000
6:158191975:AGT:A	acceptor_gain	1.0000
6:158191976:G:A	acceptor_loss	1.0000
6:158191976:G:GA	acceptor_gain	1.0000
6:158191976:GT:G	acceptor_gain	1.0000
6:158191976:GTG:G	acceptor_gain	1.0000
6:158191976:GTGAT:G	acceptor_gain	1.0000
6:158192090:TTA:T	donor_gain	1.0000
6:158192106:GCGA:G	donor_gain	1.0000
6:158192110:G:GG	donor_gain	1.0000
6:158168425:A:T	donor_gain	0.9900
6:158170468:A:AG	acceptor_gain	0.9900
6:158170469:G:GG	acceptor_gain	0.9900
6:158170469:GC:G	acceptor_gain	0.9900
6:158191973:ACAGT:A	acceptor_gain	0.9900
6:158191976:GTGA:G	acceptor_gain	0.9900
6:158192034:G:GT	donor_gain	0.9900
6:158192076:AAT:A	donor_gain	0.9900
6:158192077:ATA:A	donor_gain	0.9900
6:158170469:GCATT:G	acceptor_gain	0.9800
6:158170534:GAATG:G	donor_gain	0.9800
6:158170535:AATG:A	donor_loss	0.9800
6:158170536:ATGGT:A	donor_loss	0.9800
6:158170537:TGG:T	donor_loss	0.9800
6:158170538:GGTT:G	donor_loss	0.9800

AlphaMissense

470 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:158170522:G:A	G7R	0.998
6:158170522:G:C	G7R	0.998
6:158192075:T:A	V45E	0.998
6:158170523:G:A	G7E	0.997
6:158191992:G:C	K17N	0.997
6:158191992:G:T	K17N	0.997
6:158192069:T:A	V43D	0.996
6:158191997:T:C	F19S	0.995
6:158192003:T:C	L21P	0.994
6:158192099:T:A	L53H	0.994
6:158192038:T:C	F33L	0.993
6:158192039:T:C	F33S	0.993
6:158192040:C:A	F33L	0.993
6:158192040:C:G	F33L	0.993
6:158192072:T:C	F44S	0.993
6:158192000:T:A	L20Q	0.992
6:158192000:T:C	L20P	0.992
6:158192099:T:C	L53P	0.991
6:158191979:A:T	D13V	0.990
6:158192057:A:T	D39V	0.990
6:158191990:A:G	K17E	0.989
6:158191991:A:C	K17T	0.989
6:158192066:A:C	H42P	0.987
6:158191979:A:G	D13G	0.986
6:158191985:C:A	A15D	0.986
6:158192000:T:G	L20R	0.986
6:158192056:G:C	D39H	0.986
6:158170537:T:C	C12R	0.985
6:158192042:T:A	I34N	0.985
6:158170532:T:A	I10K	0.984

dbSNP variants (sampled 300 via entrez): RS1000006395 (6:158193530 A>G), RS1000052596 (6:158193833 C>G), RS1000060920 (6:158187270 A>G), RS1000079229 (6:158171212 A>C,G), RS1000380760 (6:158177493 G>A), RS1000464997 (6:158175329 C>T), RS1000649892 (6:158198572 A>G), RS1000712638 (6:158169095 G>A,C), RS1000937418 (6:158196313 A>C), RS1000994470 (6:158189095 A>C), RS1000995211 (6:158183730 G>C), RS1001279551 (6:158189602 T>C), RS1001310064 (6:158182934 G>A), RS1001316447 (6:158168353 C>G), RS1001421170 (6:158176790 G>A)

Disease associations

OMIM: gene MIM:608780 | disease phenotypes: MIM:616395

GenCC curated gene-disease

Disease	Classification	Inheritance
trichothiodystrophy 3, photosensitive	Definitive	Autosomal recessive
trichothiodystrophy	Supportive	Autosomal recessive

Mondo (2): trichothiodystrophy 3, photosensitive (MONDO:0014619), trichothiodystrophy (MONDO:0018053)

Orphanet (1): Trichothiodystrophy (Orphanet:33364)

HPO phenotypes

115 total (30 of 115 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000133	Gonadal dysgenesis
HP:0000243	Trigonocephaly
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000320	Bird-like facies
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000482	Microcornea
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000509	Conjunctivitis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000565	Esotropia
HP:0000568	Microphthalmia
HP:0000601	Hypotelorism
HP:0000608	Macular degeneration
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000656	Ectropion
HP:0000670	Carious teeth
HP:0000695	Natal tooth

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003127_10	Lipoprotein (a) levels	4.000000e-10
GCST005336_6	Systemic sclerosis	5.000000e-06
GCST008369_16	Plasma anti-thyroglobulin levels	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006925	lipoprotein A measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
sodium arsenite	affects methylation, decreases expression, increases expression	3
Cyclosporine	decreases expression, increases methylation	2
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
trichostatin A	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pinosylvin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
CPG-oligonucleotide	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arecoline	decreases expression	1
Carbamazepine	affects expression	1

Cellosaurus cell lines

10 cell lines: 5 transformed cell line, 5 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2555	TTD1BR LCL	Transformed cell line	Male
CVCL_4Z72	TTD13PV LCL	Transformed cell line	Male
CVCL_4Z73	TTD14PV LCL	Transformed cell line	Male
CVCL_4Z74	GM14579	Transformed cell line	Male
CVCL_4Z79	TTD14PV	Finite cell line	Male
CVCL_4Z80	TTD13PV	Finite cell line	Male
CVCL_W046	TTD1BR	Finite cell line	Male
CVCL_ZP45	TTD1BRSV	Transformed cell line	Male
CVCL_ZP46	TTD99RO	Finite cell line
CVCL_ZP47	STUC	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001813	Not specified	COMPLETED	Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy
NCT05484570	Not specified	RECRUITING	Natural History Study for DNA Repair Disorders