HERC5

Summary

HERC5 (HECT and RLD domain containing E3 ubiquitin protein ligase 5, HGNC:24368) is a protein-coding gene on chromosome 4q22.1, encoding E3 ISG15–protein ligase HERC5 (Q9UII4). Major E3 ligase for ISG15 conjugation.

This gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and five RCC1 repeats. Pro-inflammatory cytokines upregulate expression of this gene in endothelial cells. The protein localizes to the cytoplasm and perinuclear region and functions as an interferon-induced E3 protein ligase that mediates ISGylation of protein targets. The protein also acts as a modulator of the antiviral immune response. The gene lies in a cluster of HERC family genes on chromosome 4.

Source: NCBI Gene 51191 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 161 total — 1 pathogenic
• MANE Select transcript: NM_016323

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24368
Approved symbol	HERC5
Name	HECT and RLD domain containing E3 ubiquitin protein ligase 5
Location	4q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CEB1
Ensembl gene	ENSG00000138646
Ensembl biotype	protein_coding
OMIM	608242
Entrez	51191

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000264350, ENST00000502913, ENST00000508159, ENST00000508695, ENST00000510223, ENST00000865372, ENST00000865373, ENST00000912851, ENST00000912852, ENST00000912853, ENST00000912854, ENST00000962448

RefSeq mRNA: 1 — MANE Select: NM_016323 NM_016323

CCDS: CCDS3630

Canonical transcript exons

ENST00000264350 — 23 exons

Exon	Start	End
ENSE00000801220	88504232	88504415
ENSE00000801221	88504495	88504597
ENSE00000935167	88469157	88469260
ENSE00000935169	88470614	88470673
ENSE00000935172	88462135	88462356
ENSE00000935173	88463532	88463623
ENSE00000935174	88463855	88463985
ENSE00000935175	88467059	88467204
ENSE00000969928	88457119	88457534
ENSE00000969931	88472409	88472502
ENSE00000969938	88505673	88506163
ENSE00003461386	88475841	88476030
ENSE00003481723	88500915	88500985
ENSE00003498608	88486115	88486228
ENSE00003507936	88460095	88460171
ENSE00003517384	88487069	88487179
ENSE00003562436	88489166	88489336
ENSE00003567169	88493012	88493155
ENSE00003596142	88479353	88479507
ENSE00003600949	88499926	88499992
ENSE00003639274	88468346	88468422
ENSE00003647470	88494165	88494331
ENSE00003671784	88459347	88459470

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 98.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.0050 / max 5498.8911, expressed in 1123 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48808	24.0132	1117
48809	0.9918	318

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.90	gold quality
right testis	UBERON:0004534	95.12	gold quality
sperm	CL:0000019	94.94	gold quality
testis	UBERON:0000473	94.79	gold quality
left testis	UBERON:0004533	94.60	gold quality
male germ cell	CL:0000015	94.00	gold quality
germinal epithelium of ovary	UBERON:0001304	92.14	gold quality
adult organism	UBERON:0007023	88.74	gold quality
monocyte	CL:0000576	85.34	gold quality
leukocyte	CL:0000738	85.33	gold quality
mononuclear cell	CL:0000842	85.31	gold quality
ovary	UBERON:0000992	84.80	gold quality
palpebral conjunctiva	UBERON:0001812	84.65	gold quality
body of uterus	UBERON:0009853	84.32	gold quality
left ovary	UBERON:0002119	83.68	gold quality
descending thoracic aorta	UBERON:0002345	83.42	gold quality
right ovary	UBERON:0002118	82.70	gold quality
blood	UBERON:0000178	82.40	gold quality
eye	UBERON:0000970	82.13	gold quality
choroid plexus epithelium	UBERON:0003911	82.11	gold quality
islet of Langerhans	UBERON:0000006	81.77	gold quality
calcaneal tendon	UBERON:0003701	81.77	gold quality
granulocyte	CL:0000094	81.36	gold quality
bone marrow	UBERON:0002371	81.29	gold quality
myometrium	UBERON:0001296	81.26	gold quality
thoracic aorta	UBERON:0001515	81.03	gold quality
ascending aorta	UBERON:0001496	80.87	gold quality
ectocervix	UBERON:0012249	80.70	gold quality
decidua	UBERON:0002450	80.59	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	1727.55
E-GEOD-134144	yes	27.19
E-ANND-3	yes	5.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF6, MYC

miRNA regulators (miRDB)

15 targeting HERC5, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-6806-5P	96.37	68.74	587
HSA-MIR-101-2-5P	95.96	68.62	55

Literature-anchored findings (GeneRIF, showing 23)

• Data show that HERC5, a functionally active HECT ubiquitin ligase, exhibits a tightly controlled cytosolic level under inflammatory conditions in endothelial cells. (PMID:15331633)
• HERC5/Ceb1 is involved in the conjugation of ISG15 to cellular proteins. (PMID:16815975)
• these results suggest that Herc5 functions as a general E3 ligase for protein ISGylation. (PMID:16884686)
• Overexpression of cyclin E is associated with neuroendocrine lung tumors (PMID:17471231)
• This study characterizes HERC5 as a positive regulator of innate antiviral responses, and show that it sustains IRF3 activation via a novel posttranslational modification, ISG15-ylation. (PMID:20308324)
• The E3 ligase activity of HERC5 was required for blocking HIV-1 Gag particle production and correlated with the post-translational modification of Gag with ISG15. (PMID:22093708)
• Data indicate that income was inversely related to smoking behavior, and paternally derived CEB1 mutations were dose dependently increased when the father smoked in the 6 mo before pregnancy, 0.21 vs. 0.05 in smoking and nonsmoking fathers, respectively. (PMID:23538710)
• Authors identified a second distinct mechanism by which HERC5 inhibits HIV-1 replication and demonstrate that HERC5 is evolving under strong positive selection. (PMID:24693865)
• The study reports on the NMR solution structure of a G-quadruplex formed by the CEB1 DNA G-rich fragment d(AGGGGGGAGGGAGGGTGG), harboring several G-tracts including one with six continuous guanines. (PMID:24742225)
• Results show that HERC5 gene may be involved in regulating the spread of non-small cell lung cancer tumors where the methylation of its promoter is correlated with number increase of disseminated tumor cells and metastases as well as survival decreased. (PMID:25353388)
• vIRF1 association with HERC5 altered ISG15 modification of cellular proteins, and knockdown of ISG15 augmented reactivation of KSHV from latency. (PMID:26355087)
• The inhibitory effect of ISG15 on HCV RNA replication does not require its conjugation to substrates by HERC5. (PMID:26361997)
• HERC5 plays a crucial role in HCC immune evasion and has clinical relevance as a reproducible prognostic marker for risk of tumor recurrence and survival in patients. (PMID:26653219)
• Results show that HERC5 mediates covalent ISG15 conjugation to parkin in mammalian cells and that ISG15 is conjugated to the Lys349 and Lys369 residues of parkin. (PMID:27534820)
• A synonymous mutation at rs6857425 (T-C) was present in the same region among all study groups (T-C), irrespective of their HIV status. (PMID:28737979)
• Low HERC5 expression is associated with HIV infections. (PMID:29669830)
• Weighted gene correlation network analysis identifies RSAD2, HERC5, and CCL8 as prognostic candidates for breast cancer. (PMID:31225658)
• Downregulation of HERC5 E3 ligase attenuates the ubiquitination of CtBP1 to inhibit apoptosis in colorectal cancer cells. (PMID:34147029)
• HERC5 E3 ligase mediates ISGylation of hepatitis B virus X protein to promote viral replication. (PMID:34661519)
• HERC5/IFI16/p53 signaling mediates breast cancer cell proliferation and migration. (PMID:35671810)
• The E3 ligase HERC5 promotes antimycobacterial responses in macrophages by ISGylating the phosphatase PTEN. (PMID:37279284)
• Posttranslational ISGylation of NLRP3 by HERC enzymes facilitates inflammasome activation in models of inflammation. (PMID:37651190)
• HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis. (PMID:38605423)

Cross-species orthologs

0 orthologs

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

E3 ISG15–protein ligase HERC5 — Q9UII4 (reviewed: Q9UII4)

Alternative names: Cyclin-E-binding protein 1, HECT domain and RCC1-like domain-containing protein 5

All UniProt accessions (2): Q9UII4, E9PBL0

UniProt curated annotations — full annotation on UniProt →

Function. Major E3 ligase for ISG15 conjugation. Acts as a positive regulator of innate antiviral response in cells induced by interferon. Functions as part of the ISGylation machinery that recognizes target proteins in a broad and relatively non-specific manner. Catalyzes ISGylation of IRF3 which results in sustained activation, it attenuates IRF3-PIN1 interaction, which antagonizes IRF3 ubiquitination and degradation, and boosts the antiviral response. Mediates ISGylation of the phosphatase PTEN leading to its degradation, thus alleviating its suppression of the PI3K-AKT signaling pathway and promoting the production of cytokines that facilitate bacterial clearance. Interferes with the function of key viral structural proteins such as ebolavirus structural protein VP40 or HIV-1 protein GAG. Catalyzes ISGylation of influenza A viral NS1 which attenuates virulence; ISGylated NS1 fails to form homodimers and thus to interact with its RNA targets. Catalyzes ISGylation of papillomavirus type 16 L1 protein which results in dominant-negative effect on virus infectivity. Physically associated with polyribosomes, broadly modifies newly synthesized proteins in a cotranslational manner. In an interferon-stimulated cell, newly translated viral proteins are primary targets of ISG15. Promotes parkin/PRKN ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation. (Microbial infection) Functions as an E3 ligase for ISGylation of hepatitis B virus protein X leading to enhanced viral replication due to increased interferon resistance.

Subunit / interactions. (Microbial infection) Interacts with human cytomegalovirus protein UL26; this interaction inhibits global protein ISGylation. (Microbial infection) Interacts with Kaposi’s sarcoma-associated herpesvirus protein v-IRF1; this interaction inhibits global protein ISGylation. Binds to CCNA1, CCNB1, CCND1 and CCNE1. Interacts with UBE2L6. Interacts with IRF3, this interaction is marginal in resting cells but enhanced upon viral infection. Interacts with influenza A virus NS1.

Subcellular location. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed in testis and to a lesser degree in brain, ovary and placenta. Found in most tissues at low levels.

Post-translational modifications. ISGylated.

Induction. By IFNB1/IFN-beta. In endothelial cells, by TNF, IL1B/interleukin-1B and by bacterial lipopolysaccharides (LPS), hardly induced in other cells of the vascular wall such as primary smooth muscle cells and fibroblasts. By viral infection.

RefSeq proteins (1): NP_057407* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR000569	HECT_dom	Domain
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR051709	Ub-ligase/GTPase-reg	Family
IPR058923	RCC1-like_dom	Domain

Pfam: PF00632, PF25390

UniProt features (27 total): repeat 5, sequence conflict 5, helix 5, strand 4, chain 1, sequence variant 1, mutagenesis site 1, turn 1, domain 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8Y4Z	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UII4-F1	86.34	0.58

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): 994 (glycyl thioester intermediate)

Mutagenesis-validated functional residues (1):

Position	Phenotype
994	loss of activity; no effect on irf3 interaction.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9833110	RSV-host interactions
R-HSA-9833482	PKR-mediated signaling
R-HSA-9909505	Modulation of host responses by IFN-stimulated genes

MSigDB gene sets: 254 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, XU_GH1_AUTOCRINE_TARGETS_UP, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (10): regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), ISG15-protein conjugation (GO:0032020), PKR/eIFalpha signaling (GO:0039585), innate immune response (GO:0045087), regulation of defense response to virus (GO:0050688), defense response to virus (GO:0051607), protein polyubiquitination (GO:0000209), immune system process (GO:0002376)

GO Molecular Function (6): RNA binding (GO:0003723), ubiquitin-protein transferase activity (GO:0004842), ISG15 transferase activity (GO:0042296), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Antimicrobial mechanism of IFN-stimulated genes	2
Innate Immune System	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
Class I MHC mediated antigen processing & presentation	1
Respiratory Syncytial Virus Infection Pathway	1
Interferon Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
protein modification by small protein conjugation	2
ubiquitin-like protein transferase activity	2
cytoplasm	2
cyclin-dependent protein serine/threonine kinase activity	1
regulation of protein serine/threonine kinase activity	1
modification-dependent protein catabolic process	1
integrated stress response signaling	1
immune response	1
defense response to symbiont	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
defense response to virus	1
defense response	1
response to virus	1
biological_process	1
nucleic acid binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1146 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HERC5	UBA7	P41226	943
HERC5	ISG15	P05161	942
HERC5	UBE2L6	O14933	901
HERC5	USP18	Q9UMW8	873
HERC5	MX1	P20591	748
HERC5	IFIT1	P09914	736
HERC5	UBE2E2	Q96LR5	733
HERC5	OASL	Q15646	730
HERC5	IFIT3	O14879	728
HERC5	IFIT2	P09913	722
HERC5	DDX60	Q8IY21	664
HERC5	IFIH1	Q9BYX4	663
HERC5	RIGI	O95786	658
HERC5	RSAD2	Q8WXG1	643
HERC5	IFNB1	P01574	627

IntAct

112 interactions, top by confidence:

A	B	Type	Score
RPL14	RRP8	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
NS	HERC5	psi-mi:“MI:0407”(direct interaction)	0.540
NS	HERC5	psi-mi:“MI:0915”(physical association)	0.540
RRP8	NVL	psi-mi:“MI:0914”(association)	0.530
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
ZNF2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
RPL18	NOP56	psi-mi:“MI:0914”(association)	0.530
NOP16	NAP1L1	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
CCDC59	GAPDHS	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
FOXM1	PES1	psi-mi:“MI:0914”(association)	0.500
KMT5B	HERC5	psi-mi:“MI:0915”(physical association)	0.400
NUDCD2	HERC5	psi-mi:“MI:0915”(physical association)	0.400
HERC5	UBE2E1	psi-mi:“MI:0915”(physical association)	0.370
HERC5	UBE2E2	psi-mi:“MI:0915”(physical association)	0.370
HERC5	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
Nrip3	ILVBL	psi-mi:“MI:0914”(association)	0.350
TTK	IBTK	psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
Srp72		psi-mi:“MI:0914”(association)	0.350

BioGRID (313): ISG15 (Affinity Capture-Western), HERC5 (Affinity Capture-Western), HERC5 (Affinity Capture-Western), IRF3 (Biochemical Activity), UBE2L6 (Reconstituted Complex), HERC5 (Affinity Capture-MS), HERC5 (Affinity Capture-MS), HERC5 (Affinity Capture-MS), TP53 (Affinity Capture-Western), HERC5 (Affinity Capture-MS), BECN1 (Affinity Capture-Western), HERC5 (Affinity Capture-MS), HERC5 (Affinity Capture-MS), HERC5 (Affinity Capture-MS), HERC5 (Affinity Capture-MS)

ESM2 similar proteins: B1ARD6, B1ARD8, C0IN03, C6FG12, F1M649, F1MHT9, F2Z461, G1SRW8, O95786, P09913, P0C7P3, Q08AF3, Q2EMV9, Q2TB18, Q3UP24, Q460N5, Q5K651, Q5RCY5, Q5RCZ8, Q5U311, Q5XHI4, Q61098, Q68D06, Q692V3, Q69Z37, Q6IEE8, Q6P2S7, Q6P3V7, Q6P5U7, Q6P6V7, Q6Q899, Q6QR59, Q7Z7L1, Q86VS3, Q8BIR2, Q8CAS9, Q8CBA2, Q8IVG5, Q8IVU3, Q8IXQ6

Diamond homologs: A0A8C0NGY6, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	HERC5	ubiquitination
HERC5	“up-regulates quantity by stabilization”	NME2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 124 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
Peptide chain elongation	16	26.4×	3e-17
Viral mRNA Translation	16	26.4×	3e-17
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	16	26.1×	3e-17
Selenocysteine synthesis	16	25.0×	4e-17
Eukaryotic Translation Termination	16	25.0×	4e-17
Formation of a pool of free 40S subunits	17	24.7×	1e-17
Response of EIF2AK4 (GCN2) to amino acid deficiency	17	24.5×	1e-17
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	16	24.5×	5e-17

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	17	30.0×	4e-18
ribosomal large subunit biogenesis	6	25.3×	2e-05
translation	18	17.6×	3e-15
ribosomal small subunit biogenesis	6	13.0×	1e-03
negative regulation of translation	6	11.2×	2e-03
RNA processing	5	10.4×	9e-03
rRNA processing	7	9.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	122
Likely benign	14
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
976807	Single allele	Pathogenic

SpliceAI

3491 predictions. Top by Δscore:

Variant	Effect	Δscore
4:88457530:GCCGA:G	donor_gain	1.0000
4:88457533:GA:G	donor_gain	1.0000
4:88457535:G:GG	donor_gain	1.0000
4:88459345:A:AG	acceptor_gain	1.0000
4:88459345:AGAAT:A	acceptor_gain	1.0000
4:88459346:G:GG	acceptor_gain	1.0000
4:88459346:GA:G	acceptor_gain	1.0000
4:88459346:GAAT:G	acceptor_gain	1.0000
4:88459346:GAATG:G	acceptor_gain	1.0000
4:88459469:AGGTA:A	donor_loss	1.0000
4:88459470:GGTAG:G	donor_loss	1.0000
4:88459472:T:A	donor_loss	1.0000
4:88460091:TCAG:T	acceptor_loss	1.0000
4:88460092:CAG:C	acceptor_loss	1.0000
4:88460093:A:T	acceptor_loss	1.0000
4:88460167:AAAAG:A	donor_loss	1.0000
4:88460169:AAGGT:A	donor_loss	1.0000
4:88460170:AGGTA:A	donor_loss	1.0000
4:88460172:GT:G	donor_loss	1.0000
4:88460173:T:G	donor_loss	1.0000
4:88462354:A:T	donor_gain	1.0000
4:88463529:T:G	acceptor_gain	1.0000
4:88463620:ACAGG:A	donor_loss	1.0000
4:88463621:CAGG:C	donor_loss	1.0000
4:88463624:GTGG:G	donor_loss	1.0000
4:88463625:T:A	donor_loss	1.0000
4:88463924:C:G	donor_gain	1.0000
4:88467172:TGA:T	donor_gain	1.0000
4:88467173:GAA:G	donor_gain	1.0000
4:88467174:A:T	donor_gain	1.0000

AlphaMissense

6802 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:88462275:A:C	S203R	0.993
4:88462277:C:A	S203R	0.993
4:88462277:C:G	S203R	0.993
4:88462311:T:A	W215R	0.989
4:88462311:T:C	W215R	0.989
4:88468396:A:C	S370R	0.989
4:88468398:C:A	S370R	0.989
4:88468398:C:G	S370R	0.989
4:88467105:T:C	F320L	0.987
4:88467107:T:A	F320L	0.987
4:88467107:T:G	F320L	0.987
4:88469217:T:A	W399R	0.982
4:88469217:T:C	W399R	0.982
4:88460159:G:C	A152P	0.980
4:88463873:T:C	F267L	0.979
4:88463875:C:A	F267L	0.979
4:88463875:C:G	F267L	0.979
4:88463877:G:A	G268D	0.976
4:88467109:G:A	G321D	0.976
4:88460163:T:C	L153P	0.975
4:88504299:T:C	F884L	0.975
4:88504301:T:A	F884L	0.975
4:88504301:T:G	F884L	0.975
4:88462152:T:A	W162R	0.974
4:88462152:T:C	W162R	0.974
4:88470657:A:C	S428R	0.974
4:88470659:T:A	S428R	0.974
4:88470659:T:G	S428R	0.974
4:88460153:T:C	S150P	0.973
4:88462315:G:T	G216V	0.973

dbSNP variants (sampled 300 via entrez): RS1000032832 (4:88479608 G>A,T), RS1000046443 (4:88486036 T>A), RS1000115332 (4:88478478 A>G), RS1000176425 (4:88479647 T>C), RS1000189812 (4:88499247 T>A), RS1000219464 (4:88498904 G>A), RS1000302500 (4:88492790 A>G), RS1000515848 (4:88474126 C>T), RS1000525815 (4:88497649 A>G), RS1000587558 (4:88481133 A>C), RS1000687574 (4:88490933 A>G,T), RS1000724414 (4:88490580 A>G), RS1000746393 (4:88466061 C>G), RS1000790855 (4:88492077 C>T), RS1000820003 (4:88474402 A>T)

Disease associations

OMIM: gene MIM:608242 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): autosomal dominant polycystic kidney disease (MONDO:0004691)

Orphanet (1): Autosomal dominant polycystic kidney disease (Orphanet:730)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001444_13	Pulmonary function decline	9.000000e-06
GCST005956_59	Waist-to-hip ratio adjusted for BMI	5.000000e-08
GCST005957_14	Waist-to-hip ratio adjusted for BMI (age <50)	2.000000e-06
GCST005962_35	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016891	Polycystic Kidney, Autosomal Dominant	C12.050.351.968.419.403.875.500; C12.200.777.419.403.875.500; C12.950.419.403.875.500; C16.131.077.717.500; C16.320.184.625.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
trichostatin A	affects expression, affects cotreatment, increases expression	4
Cisplatin	increases expression, affects cotreatment, affects expression, affects reaction	4
sodium arsenite	decreases expression, increases expression	3
Cyclosporine	increases expression	3
methylmercuric chloride	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Lipopolysaccharides	affects expression, increases expression, affects reaction, decreases reaction	2
Silicon Dioxide	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
afuresertib	increases expression	1
HZ-6d compound	affects binding, decreases expression	1
TL8-506	affects cotreatment, increases expression	1
tungsten carbide	affects binding, decreases expression	1
ethylbenzene	increases expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
2-xylene	increases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1FI	Abcam A-549 HERC5 KO 1	Cancer cell line	Male
CVCL_B2N2	Abcam A-549 HERC5 KO 2	Cancer cell line	Male
CVCL_E1CZ	Ubigene THP-1 HERC5 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00414440	PHASE4	COMPLETED	Efficacy, Safety and Tolerability of Everolimus in Preventing End-stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease
NCT03273413	PHASE4	ACTIVE_NOT_RECRUITING	Statin Therapy in Patients With Early Stage ADPKD
NCT03949894	PHASE4	COMPLETED	Evaluating the Safety and effectivenesS in Adult KorEaN Patients Treated With Tolvaptan for Management of Autosomal domInAnt poLycystic Kidney Disease
NCT00309283	PHASE3	COMPLETED	Somatostatin in Polycystic Kidney: a Long-term Three Year Follow up Study
NCT00346918	PHASE3	COMPLETED	Sirolimus (Rapamune®) for Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT00428948	PHASE3	COMPLETED	Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT01022424	PHASE3	COMPLETED	A Long-term Administration Study of OPC-41061 in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD) (2) [Extension of Study 156-05-002]
NCT01214421	PHASE3	COMPLETED	Tolvaptan Extension Study in Participants With ADPKD
NCT01377246	PHASE3	COMPLETED	Somatostatin In Patients With Autosomal Dominant Polycystic Kidney Disease And Moderate To Severe Renal Insufficiency
NCT01616927	PHASE3	UNKNOWN	Study of Lanreotide to Treat Polycystic Kidney Disease
NCT01853553	PHASE3	COMPLETED	Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT02115659	PHASE3	UNKNOWN	Triptolide-Containing Formulation as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT02134899	PHASE3	COMPLETED	The Efficacy of Everolimus in Reducing Total Native Kidney Volume in Polycystic Kidney Disease Transplanted Recipients
NCT02160145	PHASE3	COMPLETED	Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease
NCT02964273	PHASE3	COMPLETED	Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)
NCT03764605	PHASE3	UNKNOWN	Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease
NCT03918447	PHASE3	TERMINATED	A Trial of Bardoxolone Methyl in Patients With ADPKD - FALCON
NCT04064346	PHASE3	TERMINATED	Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease
NCT04152837	PHASE3	TERMINATED	Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease
NCT04939935	PHASE3	RECRUITING	Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)
NCT05373264	PHASE3	RECRUITING	HYDROchlorothiazide to PROTECT Polycystic Kidney Disease Patients and Improve Their Quality of Life
NCT00841568	PHASE2	COMPLETED	A Long-term Administration Study of OPC-41061 in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD) [Extension of Study 156-04-001]
NCT01210560	PHASE2	COMPLETED	Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD
NCT01336972	PHASE2	COMPLETED	Short-term Renal Hemodynamic Effects of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT01451827	PHASE2	COMPLETED	8-Week Study of Tolvaptan Dose Forms in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT01670110	PHASE2	COMPLETED	Pasireotide LAR in Severe Polycystic Liver Disease
NCT01932450	PHASE2	UNKNOWN	Radiofrequency Ablation for ADPKD Blood Pressure and Disease Progression Control
NCT02527863	PHASE2	COMPLETED	Effect of the Aquaretic Tolvaptan on Nitric Oxide System
NCT02616055	PHASE2	TERMINATED	Long-Term Treatment and Follow up of Subjects Completing 24 Months of Treatment With Tesevatinib on Study KD019-101
NCT03203642	PHASE2	COMPLETED	Study of the Efficacy and Safety of Tesevatinib in Subjects With ADPKD
NCT03487913	PHASE2	COMPLETED	The ELiSA Study - Evaluation of Lixivaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease
NCT03541447	PHASE2	COMPLETED	Tolvaptan-Octreotide LAR Combination in ADPKD
NCT04284657	PHASE2	COMPLETED	Pravastatin and Alkali Therapy in Patients With Autosomal Dominant Polycystic Kidney Disease
NCT04578548	PHASE2	TERMINATED	A Study to Evaluate the Effects of GLPG2737 in Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT05190744	PHASE2	COMPLETED	Probenecid (PB) to Treat Hereditary Nephrogenic Diabetes Insipidus (NDI), ADPKD Treated With Tolvaptan, and Severely Polyuric Patients With Previous Lithium Administration
NCT05870007	PHASE2	ENROLLING_BY_INVITATION	Atorvastatin and Alkali Therapy in Patients With Autosomal Dominant Polycystic Kidney Disease
NCT06100133	PHASE2	UNKNOWN	Treat Autosomal Dominant Polycystic Kidney Disease With Oral Ketone Ester?
NCT06289998	PHASE2	ACTIVE_NOT_RECRUITING	Study of Tamibarotene in Patients With ADPKD
NCT06435858	PHASE2	RECRUITING	Short-term Effects of an SGLT2 Inhibitor on Divalent Ions in Autosomal Dominant Polycystic Kidney Disease
NCT06800651	PHASE2	RECRUITING	Trial of JMKX003142 in Participants With Rapidly Progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD)