HERC2

Summary

HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2, HGNC:4868) is a protein-coding gene on chromosome 15q13.1, encoding E3 ubiquitin-protein ligase HERC2 (O95714). E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes.

This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16.

Source: NCBI Gene 8924 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental delay with autism spectrum disorder and gait instability (Strong, GenCC)
• GWAS associations: 92
• Clinical variants (ClinVar): 1,332 total — 16 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 112
• MANE Select transcript: NM_004667

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4868
Approved symbol	HERC2
Name	HECT and RLD domain containing E3 ubiquitin protein ligase 2
Location	15q13.1
Locus type	gene with protein product
Status	Approved
Aliases	jdf2, p528, D15F37S1
Ensembl gene	ENSG00000128731
Ensembl biotype	protein_coding
OMIM	605837
Entrez	8924

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 retained_intron, 2 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000261609, ENST00000562136, ENST00000563670, ENST00000563945, ENST00000564383, ENST00000564519, ENST00000564734, ENST00000566635, ENST00000567869, ENST00000568206, ENST00000569335, ENST00000569772, ENST00000649023, ENST00000650509

RefSeq mRNA: 1 — MANE Select: NM_004667 NM_004667

CCDS: CCDS10021

Canonical transcript exons

ENST00000261609 — 93 exons

Exon	Start	End
ENSE00000672194	28246742	28246897
ENSE00000672210	28229674	28229847
ENSE00000672211	28229460	28229596
ENSE00000883379	28245881	28246066
ENSE00000883380	28248552	28248736
ENSE00000883381	28254340	28254518
ENSE00001275726	28121346	28121429
ENSE00001275732	28125006	28125193
ENSE00001275740	28130163	28130302
ENSE00001275747	28130503	28130594
ENSE00001275755	28132100	28132261
ENSE00001275763	28132653	28132830
ENSE00001275770	28135478	28135692
ENSE00001275813	28152677	28152830
ENSE00001275816	28163094	28163285
ENSE00001275823	28167687	28167827
ENSE00001275836	28169484	28169655
ENSE00001275842	28174395	28174620
ENSE00001275847	28175512	28175656
ENSE00001275855	28176428	28176599
ENSE00001275860	28176687	28176768
ENSE00001275867	28176950	28177127
ENSE00001275876	28177419	28177509
ENSE00001275883	28178887	28179030
ENSE00001275886	28179142	28179223
ENSE00001275892	28182401	28182512
ENSE00001275897	28186577	28186752
ENSE00001275902	28190965	28191056
ENSE00001276251	28124037	28124234
ENSE00001294002	28111040	28112035
ENSE00001299639	28141731	28141846
ENSE00001302016	28144673	28144804
ENSE00001308643	28143873	28143991
ENSE00001312763	28168407	28168590
ENSE00001313253	28146237	28146344
ENSE00001315635	28117013	28117154
ENSE00001320885	28142238	28142393
ENSE00001321145	28142827	28142952
ENSE00001324865	28144077	28144235
ENSE00001328154	28141432	28141630
ENSE00001494211	28322075	28322179
ENSE00001594984	28238114	28238217
ENSE00001601100	28206240	28206382
ENSE00001606066	28215621	28215802
ENSE00001623761	28233146	28233341
ENSE00001624156	28202347	28202614
ENSE00001633210	28212445	28212583
ENSE00001634587	28238602	28238772
ENSE00001635918	28211002	28211145
ENSE00001638011	28218489	28218671
ENSE00001663884	28220452	28220644
ENSE00001674960	28214655	28214802
ENSE00001700117	28234070	28234284
ENSE00001721873	28214076	28214272
ENSE00001725691	28230367	28230500
ENSE00001729623	28233434	28233561
ENSE00001733476	28236963	28237113
ENSE00001734407	28222028	28222215
ENSE00001744235	28299402	28299516
ENSE00001766055	28233664	28233796
ENSE00001774942	28229195	28229346
ENSE00001802061	28213742	28213972
ENSE00003459473	28280068	28280287
ENSE00003463848	28268465	28268616
ENSE00003473156	28196461	28196569
ENSE00003486976	28228218	28228409
ENSE00003487503	28292888	28293022
ENSE00003509269	28265817	28265974
ENSE00003514203	28201456	28201554
ENSE00003514955	28113071	28113283
ENSE00003523102	28262918	28263169
ENSE00003531123	28114612	28114802
ENSE00003533474	28196215	28196354
ENSE00003536055	28260777	28260970
ENSE00003556072	28269248	28269436
ENSE00003557272	28274291	28274447
ENSE00003559254	28198378	28198503
ENSE00003559866	28265618	28265731
ENSE00003560366	28257061	28257261
ENSE00003567743	28191139	28191244
ENSE00003580219	28270695	28270868
ENSE00003594809	28113573	28113678
ENSE00003597239	28256089	28256317
ENSE00003599109	28191961	28192151
ENSE00003601325	28274905	28275005
ENSE00003618575	28116665	28116859
ENSE00003645688	28272894	28273004
ENSE00003646934	28255872	28255996
ENSE00003655270	28321362	28321464
ENSE00003662130	28202113	28202249
ENSE00003666202	28272215	28272386
ENSE00003682976	28198601	28198769
ENSE00003690491	28115429	28115541

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 95.63.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.17	gold quality
cerebellar cortex	UBERON:0002129	94.80	gold quality
cerebellar hemisphere	UBERON:0002245	94.80	gold quality
cerebellum	UBERON:0002037	94.79	gold quality
pituitary gland	UBERON:0000007	94.72	gold quality
corpus callosum	UBERON:0002336	94.57	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.53	gold quality
adenohypophysis	UBERON:0002196	94.47	gold quality
superior frontal gyrus	UBERON:0002661	94.45	gold quality
right frontal lobe	UBERON:0002810	94.38	gold quality
frontal cortex	UBERON:0001870	94.25	gold quality
frontal lobe	UBERON:0016525	94.25	gold quality
prefrontal cortex	UBERON:0000451	94.18	gold quality
primary visual cortex	UBERON:0002436	94.07	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.05	gold quality
right ovary	UBERON:0002118	93.99	gold quality
left ovary	UBERON:0002119	93.90	gold quality
lower esophagus	UBERON:0013473	93.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.78	gold quality
peripheral nervous system	UBERON:0000010	93.75	gold quality
nerve	UBERON:0001021	93.75	gold quality
tibial nerve	UBERON:0001323	93.75	gold quality
brain	UBERON:0000955	93.70	gold quality
cerebral cortex	UBERON:0000956	93.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.65	gold quality
ovary	UBERON:0000992	93.50	gold quality
telencephalon	UBERON:0001893	93.47	gold quality
skeletal muscle tissue	UBERON:0001134	93.46	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.02
E-MTAB-4850	no	78.85

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HLTF, LEF1, MITF

miRNA regulators (miRDB)

66 targeting HERC2, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267

Literature-anchored findings (GeneRIF, showing 40)

• Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression (PMID:18172690)
• We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. (PMID:18252221)
• A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. (PMID:18252222)
• Single nucleotide polymorphism in HERC2 gene is associated with ulcerative colitis (PMID:18438405)
• OCA2 and HERC2 have roles in hair color in Australian adolescents (PMID:18528436)
• Results confirmed the association of HERC2 rs12913832 with eye colour and showed that this SNP is also significantly associated with skin and hair colouration. (PMID:19208107)
• Two single nucleotide polymorphisms found in intron 86 (rs12913832) and the 3’ UTR region (rs1129038) of the HERC2 gene. (PMID:19472299)
• The circadian oscillation of XPA is achieved both by regulation of transcription by the core circadian clock proteins including cryptochrome and by regulation at the posttranslational level by the HERC2 ubiquitin ligase. (PMID:20304803)
• ). Sequence variations in rs11636232 and rs7170852 in HERC2, rs1800407 in OCA2 and rs16891982 in MATP showed additional association with eye colours (PMID:20457063)
• role in pigmentation characteristics in Spanish population (PMID:20629734)
• Findings identify a function for HERC2 in regulating BRCA1 stability in opposition to BARD1. The HERC2 expression in breast epithelial cells and breast carcinomas suggests that this mechanism may play a role in breast carcinogenesis. (PMID:20631078)
• Data show that Mc1R, HERC2, IRF4, TYR and EXOC2 are ranked highest in hair color prediction analysis. (PMID:21197618)
• HERC2 acts as a regulator of E6AP. (PMID:21493713)
• These results suggest that HERC2 regulates DNA replication progression and origin firing by facilitating MCM2 phosphorylation. (PMID:21775519)
• we found somatic mutations of HERC2, HERC3, TRIP12, UBE2Q1 and UBE4B genes in gastric carcinoma and colorectal carcinomas with microsatellite instability (PMID:22124266)
• HERC2 rs12913832 region functions as an enhancer regulating OCA2 transcription. (PMID:22234890)
• the NEURL4-HERC2 complex participates in the ubiquitin-dependent regulation of centrosome architecture (PMID:22261722)
• In response to double-strand breaks, both HERC2 and RNF168 were specifically modified with SUMO1 at double-strand break sites in a manner dependent on the SUMO E3 ligase PIAS4. (PMID:22508508)
• Pathogenic changes in HERC2 are associated with nonsyndromic intellectual disability, autism, and gait disturbance. (PMID:23065719)
• ATR-mediated phosphorylation induces XPA stabilization by antagonizing HERC2-catalyzed XPA ubiquitination. (PMID:23178497)
• Studied an autosomal-recessive neurodevelopmental disorder with some phenotypic similarities to Angelman syndrome, found among the Old Order Amish. Our molecular investigation identified a mutation in HERC2 associated with the disease phenotype. (PMID:23243086)
• given a particular HERC2/OCA2 genotype, males are more prone to have lighter eye colors than predicted by their genotypes, while females tend to have darker eye colors than predicted (PMID:23601698)
• Results identify HERC2 as a regulator of p53 signaling. (PMID:24722987)
• results thus suggest that HERC2 regulates the basal turnover of FBXL5, and that this ubiquitin-dependent degradation pathway contributes to the control of mammalian iron metabolism (PMID:24778179)
• identified HERC2, a HECT domain-containing E3 ligase, as being responsible for polyubiquitination of USP33. (PMID:24855649)
• Data show that histone H2A deubiquitinase USP16 interacts with E3 ubiquitin-protein ligase HERC2, negatively regulates DNA damage-induced ubiquitin foci formation, and is required for termination of the ubiquitin signal. (PMID:25305019)
• SNP rs12913832 in HERC2 was found to be strongly associated with blue eye colour. SNP associations with hair and skin colour were weaker and genotypes less predictive. (PMID:26286644)
• Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. (PMID:26436293)
• By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis (PMID:27259994)
• We showed that loss of HERC2 function leads to the accumulation of XPA and BRCA1 in the patient’s fibroblasts and generates decreased sensitivity to apoptosis and increased level of DNA repair (PMID:27759030)
• Evaluated the association of seven OCA2-HERC2 SNPs and haplotypes with pigmentation characteristics (eye, skin, hair and freckles) in the highly admixed and phenotypically heterogeneous Brazilian population. Such SNPs and haplotypes could be deemed as good predictors for the presence of freckles and for skin, eye and hair pigmentation in the Brazilian population. (PMID:28081795)
• The results of this study are the first to show an association between HERC2 variants and time to first cSCC post-transplant. (PMID:28456133)
• HERC2 is a master regulator of G-quadruplex, a DNA secondary structure that triggers genomic instability, through BLM, WRN, and RPA, and may serve as a potential molecular target in cancer therapy (PMID:30279242)
• analysis of the HERC2-associated proteome revealed striking differential protein expression between neurodevelopmental disorder cases and controls (PMID:30902390)
• Study found that a partial duplication of a well-characterized gene, the HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 2 gene (HERC2) (esv3635993) showed apparently higher allele frequency differentiation from the other gene duplications as well as the majority of random SNVs analyzed as a null background. (PMID:31124564)
• NudC-like protein 2 restrains centriole amplification by stabilizing HERC2. (PMID:31427565)
• HERC2 regulates RPA2 by mediating ATR-induced Ser33 phosphorylation and ubiquitin-dependent degradation. (PMID:31582797)
• Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2. (PMID:31665549)
• Identification of rare missense mutations in NOTCH2 and HERC2 associated with familial central precocious puberty via whole-exome sequencing. (PMID:32400230)
• Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality. (PMID:32571899)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	herc2	ENSDARG00000073841
mus_musculus	Herc2	ENSMUSG00000030451
rattus_norvegicus	Herc2	ENSRNOG00000013718
drosophila_melanogaster	HERC2	FBGN0031107

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), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

E3 ubiquitin-protein ligase HERC2 — O95714 (reviewed: O95714)

Alternative names: HECT domain and RCC1-like domain-containing protein 2, HECT-type E3 ubiquitin transferase HERC2

All UniProt accessions (4): O95714, A0A3B3IRP6, H3BRG9, H3BUQ1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes. Recruited to sites of DNA damage in response to ionizing radiation (IR) and facilitates the assembly of UBE2N and RNF8 promoting DNA damage-induced formation of ‘Lys-63’-linked ubiquitin chains. Acts as a mediator of binding specificity between UBE2N and RNF8. Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of XPA which influences the circadian oscillation of DNA excision repair activity. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway. Also modulates iron metabolism by regulating the basal turnover of FBXL5.

Subunit / interactions. Interacts (when phosphorylated at Thr-4827 and sumoylated) with RNF8 (via FHA domain); this interaction increases after ionizing radiation (IR) treatment. Interacts with XPA. Interacts with NEURL4. Via its interaction with NEURL4, may indirectly interact with CCP110 and CEP97.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Centriole. Nucleus.

Post-translational modifications. Phosphorylation at Thr-4827 is required for interaction with RNF8. Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs), promoting the interaction with RNF8.

Disease relevance. Intellectual developmental disorder, autosomal recessive 38 (MRT38) [MIM:615516] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT38 is characterized by global developmental delay affecting motor, speech, adaptive, and social development. Patients manifest autistic features, aggression, self-injury, impulsivity, and distractibility. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ZZ-type zinc finger mediates binding to SUMO1, and at low level SUMO2. The RCC1 repeats are grouped into three seven-bladed beta-propeller regions.

Pathway. Protein modification; protein ubiquitination.

Polymorphism. Genetic variants in HERC2 define the skin/hair/eye pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as skin/hair/eye pigmentation type 1, blue/nonblue eyes or skin/hair/eye pigmentation type 1, blue/brown eyes or skin/hair/eye pigmentation type 1, blond/brown hair or eye color, brown/blue or eye color, blue/nonblue or eye color type 3 (EYCL3) or brown eye color type 2 (BEY2) or hair color type 3 (HCL3). Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair. All blue-eyed individuals share a common haplotype, consisting of variants rs1129038 and rs12913832, independently of their origin (Denmark, Turkey or Jordan), suggesting a founder effect. This haplotype is located within HERC2 gene intron 86 and may be part of a regulatory element, which controls neighboring OCA2 gene expression. The blue eye-associated haplotype tends to silence OCA2 gene expression. Other variants have also been statistically associated with eye color.

RefSeq proteins (1): NP_004658* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR000433	Znf_ZZ	Domain
IPR000569	HECT_dom	Domain
IPR001199	Cyt_B5-like_heme/steroid-bd	Domain
IPR004939	APC_su10/DOC_dom	Domain
IPR006624	Beta-propeller_rpt_TECPR	Repeat
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR010606	Mib_Herc2	Domain
IPR014722	Rib_uL2_dom2	Homologous_superfamily
IPR021097	CPH_domain	Domain
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036400	Cyt_B5-like_heme/steroid_sf	Homologous_superfamily
IPR037252	Mib_Herc2_sf	Homologous_superfamily
IPR037976	HERC2_APC10	Domain
IPR041987	ZZ_HERC2	Domain
IPR043145	Znf_ZZ_sf	Homologous_superfamily
IPR051625	Signaling_Regulatory_Domain	Family
IPR058923	RCC1-like_dom	Domain

Pfam: PF00173, PF00415, PF00569, PF00632, PF03256, PF06701, PF11515, PF25390

UniProt features (240 total): strand 113, helix 46, repeat 21, sequence conflict 12, modified residue 11, binding site 8, compositionally biased region 7, domain 5, region of interest 5, turn 4, mutagenesis site 3, chain 1, zinc finger region 1, coiled-coil region 1, active site 1, sequence variant 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
9L93	X-RAY DIFFRACTION	1.73
3KCI	X-RAY DIFFRACTION	1.8
9L8Y	X-RAY DIFFRACTION	1.92
7Q42	X-RAY DIFFRACTION	1.95
7RGW	X-RAY DIFFRACTION	1.99
6WW3	X-RAY DIFFRACTION	2.1
7Q45	X-RAY DIFFRACTION	2.1
7Q44	X-RAY DIFFRACTION	2.2
6WW4	X-RAY DIFFRACTION	2.25
7Q40	X-RAY DIFFRACTION	2.35
7Q43	X-RAY DIFFRACTION	2.4
7Q46	X-RAY DIFFRACTION	2.46
4L1M	X-RAY DIFFRACTION	2.6
7Q41	X-RAY DIFFRACTION	3.01
2KEO	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for O95714 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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): 4762 (glycyl thioester intermediate)

Ligand- & substrate-binding residues (8): 2708; 2711; 2723; 2726; 2732; 2735; 2741; 2745

Post-translational modifications (11): 272, 647, 1577, 1942, 1944, 2454, 2928, 4810, 4811, 4814, 4827

Mutagenesis-validated functional residues (3):

Position	Phenotype
2708	abolishes binding to sumo; when associated with s-2711.
2711	abolishes binding to sumo; when associated with s-2708.
4827	prevents herc2 c-terminal fragment binding to endogenous rnf8.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 437 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GCM_MAP4K4, GCM_PTPRD, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, chr15q13, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TATTATA_MIR374, GOBP_NEUROGENESIS, GOBP_MALE_GAMETE_GENERATION, MODULE_308

GO Biological Process (9): DNA repair (GO:0006281), intracellular protein transport (GO:0006886), DNA damage response (GO:0006974), spermatogenesis (GO:0007283), protein ubiquitination (GO:0016567), neuron differentiation (GO:0030182), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of Notch signaling pathway (GO:0045746), protein stabilization (GO:0050821)

GO Molecular Function (9): guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), SUMO binding (GO:0032183), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centriole (GO:0005814), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1
DNA Double Strand Break Response	1
DNA Double-Strand Break Repair	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
G2/M Checkpoints	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membraneless organelle	2
DNA metabolic process	1
DNA damage response	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
cellular response to stress	1
developmental process involved in reproduction	1
male gamete generation	1
protein modification by small protein conjugation	1
cell differentiation	1
generation of neurons	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
regulation of protein stability	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
ubiquitin-like protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
microtubule organizing center	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1859 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HERC2	HLTF	Q14527	811
HERC2	OCA2	Q04671	793
HERC2	RABGGTA	Q92696	767
HERC2	NEURL4	Q96JN8	651
HERC2	UBE3A	P78355	525
HERC2	MAPK6	Q16659	507
HERC2	TRIM36	Q9NQ86	462
HERC2	STK11	Q15831	437
HERC2	UBR4	Q5T4S7	423
HERC2	LRIF1	Q5T3J3	421
HERC2	RMND5A	Q9H871	419
HERC2	IL31RA	Q8NI17	416
HERC2	MAGEB6B	A0A0J9YX57	367
HERC2	RANBP10	Q6VN20	366
HERC2	USP32	Q8NFA0	365

IntAct

262 interactions, top by confidence:

A	B	Type	Score
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
PSMD2	PSMD11	psi-mi:“MI:0914”(association)	0.730
XPA	HERC2	psi-mi:“MI:0914”(association)	0.680
XPA	HERC2	psi-mi:“MI:0915”(physical association)	0.680
HERC2	SPZ1	psi-mi:“MI:0915”(physical association)	0.670
PSMC4	PSMD11	psi-mi:“MI:0914”(association)	0.670
FAM98A	HERC2	psi-mi:“MI:0914”(association)	0.640
AIPL1	PDE5A	psi-mi:“MI:0914”(association)	0.640
EIF3L	EIF3F	psi-mi:“MI:0914”(association)	0.640
FBXL5	HERC2	psi-mi:“MI:0915”(physical association)	0.620
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
ARID3A	ARID3C	psi-mi:“MI:0914”(association)	0.530
SOST	KPNA4	psi-mi:“MI:0914”(association)	0.530
RNF166	MPDZ	psi-mi:“MI:0914”(association)	0.530
SPZ1	GAPDHS	psi-mi:“MI:0914”(association)	0.530
KNOP1	DHX15	psi-mi:“MI:0914”(association)	0.530
APBA2	HERC2	psi-mi:“MI:0914”(association)	0.530
DNAJA1	HERC2	psi-mi:“MI:0914”(association)	0.530
NCOA4	HERC2	psi-mi:“MI:0914”(association)	0.530
MAPK6	ECI2	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
DISC1	AP4M1	psi-mi:“MI:0914”(association)	0.530

BioGRID (722): HERC2 (Affinity Capture-Western), HERC2 (Affinity Capture-Western), USP16 (Affinity Capture-Western), HERC2 (Affinity Capture-MS), HERC2 (Affinity Capture-Western), HERC2 (Affinity Capture-MS), HERC2 (Affinity Capture-MS), HERC2 (Affinity Capture-MS), HERC2 (Affinity Capture-MS), BIRC6 (Affinity Capture-MS), GET4 (Affinity Capture-MS), FAM63A (Affinity Capture-MS), RIPK1 (Affinity Capture-MS), RNF115 (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS)

ESM2 similar proteins: A2VDJ0, A2VE78, A4D1B5, A6NFN9, D3YYM4, O15040, O95714, O95876, Q3MJ13, Q3U1D0, Q3U3D7, Q3U3S3, Q3UFT3, Q4AC94, Q4KM95, Q4U2R1, Q52KB6, Q562E2, Q5F479, Q5R6E1, Q5RFQ4, Q5SUS0, Q5XGI3, Q5XX13, Q6GQ34, Q6INS1, Q6NRE4, Q6P2C0, Q6ZPF3, Q7TP65, Q86VV8, Q8BPN8, Q8C0W1, Q8C2S5, Q8IV35, Q8IVF5, Q8NDB2, Q8NG48, Q8R2U7, Q8R3C1

Diamond homologs: A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4F6W9, B8N7E5, D3ZBM7, E1B7Q7, E1C656, F1LP64, F1N6G5, F1RCR6, F8W2M1, G0S9J5, G5E870, O00308, O08759, O13834, O14326, O15033, O17736, O95714, P39940, P40985, P46934, P46935, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q13526, Q14669, Q15034, Q15386, Q15751

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
HERC2	down-regulates	XPA	ubiquitination
Ub:E2	“up-regulates activity”	HERC2	ubiquitination
HERC2	“down-regulates quantity by destabilization”	NEURL4	polyubiquitination
HERC2	“down-regulates quantity”	USP20	ubiquitination
HERC2	“down-regulates quantity by destabilization”	BRCA1	ubiquitination
HERC2	“down-regulates quantity by destabilization”	USP20	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 212 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
Defective CFTR causes cystic fibrosis	7	11.7×	3e-04
The role of GTSE1 in G2/M progression after G2 checkpoint	9	11.1×	3e-05
Regulation of activated PAK-2p34 by proteasome mediated degradation	5	10.6×	2e-03
Regulation of ornithine decarboxylase (ODC)	5	10.4×	2e-03
Vpu mediated degradation of CD4	5	10.1×	2e-03
Autodegradation of the E3 ubiquitin ligase COP1	5	10.1×	2e-03
Ubiquitin-dependent degradation of Cyclin D	5	10.1×	2e-03
Cross-presentation of soluble exogenous antigens (endosomes)	5	9.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	31.2×	4e-04
mitotic spindle organization	7	10.6×	2e-03
protein deubiquitination	8	7.9×	3e-03
mitochondrial translation	7	6.8×	1e-02
mitotic cell cycle	8	5.9×	9e-03
cell division	14	3.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1332 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	16
Uncertain significance	859
Likely benign	246
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013064	NM_004667.6(HERC2):c.637C>T (p.Arg213Ter)	Pathogenic
1342429	NM_004667.6(HERC2):c.1168C>T (p.Arg390Ter)	Pathogenic
148881	GRCh38/hg38 15q11.2-13.1(chr15:22358243-28481444)x4	Pathogenic
152908	GRCh38/hg38 15q12-13.1(chr15:27713721-28154050)x3	Pathogenic
1808643	GRCh37/hg19 15q11.2-13.1(chr15:23615769-28545601)x3	Pathogenic
2039450	NM_004667.6(HERC2):c.2797_2798del (p.Leu933fs)	Pathogenic
2425198	NC_000015.9:g.(?28475513)(28475646_?)del	Pathogenic
2663786	NC_000015.10:g.(?23319714)(28314256_?)del	Pathogenic
2685503	GRCh37/hg19 15q11.2-13.1(chr15:23615769-28915864)x1	Pathogenic
3256291	NM_004667.6(HERC2):c.12988C>T (p.Gln4330Ter)	Pathogenic
3374853	NM_004667.6(HERC2):c.2834_2835dup (p.Ala947fs)	Pathogenic
374155	NM_004667.6(HERC2):c.6976del (p.Ile2325_Leu2326insTer)	Pathogenic
522952	NM_004667.6(HERC2):c.9710T>A (p.Leu3237Ter)	Pathogenic
58635	GRCh38/hg38 15q11.2-13.1(chr15:23537429-28275167)x1	Pathogenic
88738	NM_004667.6(HERC2):c.1781C>T (p.Pro594Leu)	Pathogenic
931703	NM_004667.6(HERC2):c.11701-1G>A	Pathogenic
1690901	NM_004667.6(HERC2):c.4352-1G>A	Likely pathogenic
1696690	NM_004667.6(HERC2):c.13279C>T (p.Arg4427Ter)	Likely pathogenic
2425199	NC_000015.9:g.(?28544548)(28544662_?)dup	Likely pathogenic
2444380	NM_004667.6(HERC2):c.12787_12791dup (p.Thr4265fs)	Likely pathogenic
2503137	NM_004667.6(HERC2):c.11218C>T (p.Arg3740Ter)	Likely pathogenic
2506308	NC_000015.9:g.(28538169_28544547)_(28544663_28566507)dup	Likely pathogenic
2691672	NC_000015.9:g.(28414802_28419540)_(28419767_28420657)dup	Likely pathogenic
3065359	NM_004667.6(HERC2):c.7704_7716+5del	Likely pathogenic
3258088	NM_004667.6(HERC2):c.592C>T (p.Arg198Ter)	Likely pathogenic
3383163	NM_004667.6(HERC2):c.12923del (p.Cys4308fs)	Likely pathogenic
3901544	NM_004667.6(HERC2):c.5846-1G>A	Likely pathogenic
4278345	NM_004667.6(HERC2):c.7070-1G>C	Likely pathogenic
4686012	NM_004667.6(HERC2):c.13450G>A (p.Glu4484Lys)	Likely pathogenic
4820128	NC_000015.9:g.23679391_28551391dup	Likely pathogenic

SpliceAI

15779 predictions. Top by Δscore:

Variant	Effect	Δscore
15:28112032:ACAC:A	acceptor_gain	1.0000
15:28112033:CAC:C	acceptor_gain	1.0000
15:28112033:CACC:C	acceptor_gain	1.0000
15:28112034:AC:A	acceptor_gain	1.0000
15:28112035:CC:C	acceptor_gain	1.0000
15:28112035:CCTG:C	acceptor_loss	1.0000
15:28112036:C:CC	acceptor_gain	1.0000
15:28112037:T:A	acceptor_loss	1.0000
15:28112044:C:CT	acceptor_gain	1.0000
15:28112045:A:T	acceptor_gain	1.0000
15:28113065:GCCTA:G	donor_loss	1.0000
15:28113066:CCTAC:C	donor_loss	1.0000
15:28113068:TA:T	donor_loss	1.0000
15:28113070:C:G	donor_loss	1.0000
15:28113285:T:G	acceptor_loss	1.0000
15:28114609:AACCT:A	donor_loss	1.0000
15:28114610:A:AT	donor_loss	1.0000
15:28114611:CCTAT:C	donor_loss	1.0000
15:28114637:A:AC	donor_gain	1.0000
15:28114638:C:CC	donor_gain	1.0000
15:28114638:CT:C	donor_gain	1.0000
15:28114798:TCAAC:T	acceptor_gain	1.0000
15:28114799:CAAC:C	acceptor_gain	1.0000
15:28114799:CAACC:C	acceptor_gain	1.0000
15:28114802:CC:C	acceptor_loss	1.0000
15:28114802:CCT:C	acceptor_gain	1.0000
15:28114803:C:A	acceptor_loss	1.0000
15:28114803:C:CC	acceptor_gain	1.0000
15:28114804:T:C	acceptor_gain	1.0000
15:28114804:T:TC	acceptor_gain	1.0000

AlphaMissense

31504 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:28111878:G:T	A4797D	1.000
15:28111887:T:A	D4794V	1.000
15:28111887:T:C	D4794G	1.000
15:28111887:T:G	D4794A	1.000
15:28111888:C:A	D4794Y	1.000
15:28111888:C:G	D4794H	1.000
15:28111894:C:G	D4792H	1.000
15:28111896:A:C	I4791R	1.000
15:28111896:A:T	I4791K	1.000
15:28111904:G:C	C4788W	1.000
15:28111905:C:A	C4788F	1.000
15:28111905:C:T	C4788Y	1.000
15:28111906:A:G	C4788R	1.000
15:28111917:G:T	A4784D	1.000
15:28111926:A:G	L4781P	1.000
15:28111938:A:G	L4777P	1.000
15:28111957:A:C	Y4771D	1.000
15:28111962:G:T	P4769H	1.000
15:28111969:T:C	K4767E	1.000
15:28111971:A:G	L4766P	1.000
15:28111976:G:C	F4764L	1.000
15:28111976:G:T	F4764L	1.000
15:28111978:A:G	F4764L	1.000
15:28111978:A:T	F4764I	1.000
15:28111979:G:C	F4763L	1.000
15:28111979:G:T	F4763L	1.000
15:28111981:A:G	F4763L	1.000
15:28111982:A:C	C4762W	1.000
15:28111983:C:T	C4762Y	1.000
15:28111984:A:G	C4762R	1.000

dbSNP variants (sampled 300 via entrez): RS1000004640 (15:28150073 C>T), RS1000008637 (15:28255907 A>C), RS1000009522 (15:28310239 A>G), RS1000021985 (15:28161472 T>C), RS1000034959 (15:28161661 C>T), RS1000066004 (15:28301134 G>A), RS1000087651 (15:28141804 T>C), RS1000098127 (15:28301554 C>T), RS1000103719 (15:28223759 G>T), RS1000125755 (15:28194620 G>C,T), RS1000131553 (15:28180622 T>C), RS1000160184 (15:28237283 G>A), RS1000169699 (15:28116414 A>G), RS1000199879 (15:28263758 A>G), RS1000211427 (15:28192727 T>C)

Disease associations

OMIM: gene MIM:605837 | disease phenotypes: MIM:615516, MIM:176270, MIM:105830, MIM:618330

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental delay with autism spectrum disorder and gait instability	Strong	Autosomal recessive

Mondo (4): developmental delay with autism spectrum disorder and gait instability (MONDO:0014224), Prader-Willi syndrome (MONDO:0008300), Angelman syndrome (MONDO:0007113), global developmental delay with or without impaired intellectual development (MONDO:0032680)

Orphanet (3): Developmental delay with autism spectrum disorder and gait instability (Orphanet:329195), Prader-Willi syndrome (Orphanet:739), Angelman syndrome (Orphanet:72)

HPO phenotypes

112 total (30 of 112 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000189	Narrow palate
HP:0000219	Thin upper lip vermilion
HP:0000268	Dolichocephaly
HP:0000303	Mandibular prognathia
HP:0000341	Narrow forehead
HP:0000446	Narrow nasal bridge
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000582	Upslanted palpebral fissure
HP:0000635	Blue irides
HP:0000670	Carious teeth
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000742	Self-mutilation
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000786	Primary amenorrhea

GWAS associations

92 associations (top):

Study	Trait	p-value
GCST000146_1	Iris color	1.000000e-43
GCST000190_4	Black vs. blond hair color	4.000000e-103
GCST000191_1	Black vs. red hair color	1.000000e-77
GCST000685_2	Eye color traits	1.000000e-300
GCST001509_3	Vitiligo	4.000000e-08
GCST001723_1	Eye color	2.000000e-20
GCST001929_4	Eye color	1.000000e-177
GCST001929_7	Eye color	1.000000e-158
GCST001932_5	Hair color	1.000000e-167
GCST001939_3	Tanning	1.000000e-22
GCST002875_33	Diisocyanate-induced asthma	7.000000e-14
GCST002906_1	Skin colour saturation	4.000000e-14
GCST002907_2	Perceived skin darkness	4.000000e-77
GCST002908_2	Skin sensitivity to sun	2.000000e-07
GCST003021_6	Brown vs. non-brown hair color	4.000000e-09
GCST003022_6	Light vs. dark hair color	5.000000e-14
GCST003023_5	Blond vs non-blond hair color	2.000000e-14
GCST003327_4	Squamous cell carcinoma	3.000000e-09
GCST003479_1	Hair color	5.000000e-104
GCST003996_4	Monobrow	5.000000e-47
GCST004661_2	Uveal melanoma	5.000000e-07
GCST004785_31	Vitiligo	9.000000e-14
GCST005149_12	Colorectal cancer	4.000000e-07
GCST005790_33	Rosacea symptom severity	4.000000e-12
GCST005790_34	Rosacea symptom severity	7.000000e-10
GCST005897_43	Low tan response	6.000000e-184
GCST006075_20	Hair color	1.000000e-100
GCST006986_7	Red vs. brown/black hair color	3.000000e-113
GCST006988_1	Blond vs. brown/black hair color	2.000000e-308
GCST006988_167	Blond vs. brown/black hair color	8.000000e-12

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0003949	eye color
EFO:0003924	hair color
EFO:0004279	suntan
EFO:0006995	response to diisocyanate
EFO:0007906	synophrys measurement
EFO:0009180	rosacea severity measurement
EFO:1002040	Corneal astigmatism
EFO:0009764	eye colour measurement
EFO:0010176	keratinocyte carcinoma
EFO:0007621	bone mineral content measurement
EFO:0004695	intraocular pressure measurement
EFO:0004632	nevus count
EFO:0004502	adiponectin measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D017204	Angelman Syndrome	C10.228.662.075; C16.131.077.095; C16.131.260.040; C16.320.180.040; C16.320.447.250
D011218	Prader-Willi Syndrome	C10.597.606.360.690; C16.131.077.730; C16.131.260.700; C16.320.180.700; C16.320.447.500; C18.654.726.750.500.740
C531619	Happy puppet syndrome (formerly) (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	decreases expression, increases abundance, affects cotreatment	1
bisphenol A	affects cotreatment, decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
(+)-JQ1 compound	increases expression	1
Temozolomide	decreases expression	1
Leflunomide	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Aldehydes	decreases expression	1
Atrazine	decreases expression	1
Benzene	decreases expression	1
Caffeine	increases phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01298180	PHASE4	COMPLETED	Is There a Sensibility Increased in the Growth Hormone at Child With Prader-Willi Syndrome?
NCT01542242	PHASE4	TERMINATED	Liraglutide Use in Prader-Willi Syndrome
NCT03031626	PHASE4	COMPLETED	Oxygen Versus Medical Air for Treatment of CSA in Prader Will Syndrome
NCT03616509	PHASE4	COMPLETED	GH in Adults With PWS, Effect on Hypotonia Evaluated by Functional MRI, Relationship With Strength and Body Composition
NCT04066088	PHASE4	WITHDRAWN	Dose Clinical Trial of Guanfacine Extended Release for the Reduction of Aggression and Self-injuries Behavior Associated With Prader-Willi Syndrome
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT06901245	PHASE4	RECRUITING	Tirzepatide in PWS, HO and GNSO
NCT00175305	PHASE3	TERMINATED	Prader-Willi Syndrome and Appetite
NCT00444964	PHASE3	COMPLETED	Growth Hormone Use in Adults With Prader-Willi Syndrome
NCT00603109	PHASE3	TERMINATED	Effect of Rimonabant on Weight Gain and Body Composition in Adults With Prader Willi Syndrome
NCT02179151	PHASE3	TERMINATED	Double-Blind, Placebo Controlled, Phase 3 Trial of ZGN-440 (Beloranib) in Obese Subjects With Prader-Willi Syndrome
NCT02204163	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Eutropin in Prader-Willi Syndrome
NCT02810483	PHASE3	TERMINATED	Study of the Efficacy of Topiramate in Patients With Prader Willi Syndrome Over 8 Weeks
NCT03440814	PHASE3	COMPLETED	A Study of Diazoxide Choline in Patients With Prader-Willi Syndrome
NCT03554031	PHASE3	UNKNOWN	A Study to Evaluate the Efficacy and Safety of Recombinant Human Growth Hormone Injection in Patients With Prader-Willi Syndrome
NCT03649477	PHASE3	COMPLETED	Phase 3 Study of Intranasal Carbetocin (LV-101) in Patients With Prader-Willi Syndrome
NCT03714373	PHASE3	COMPLETED	Open-Label Extension Study of DCCR in PWS Followed by Double-Blind, Placebo-Controlled, Randomized Withdrawal Period
NCT04086810	PHASE3	WITHDRAWN	An Open-Label Study of DCCR Tablet in Patients With PWS
NCT04283578	PHASE3	COMPLETED	Oxytocin Treatment in Neonates and Infants With Prader-Willi Syndrome
NCT04697381	PHASE3	COMPLETED	Study of the Efficacy and Safety of Somatropin in Japanese Participants With PWS
NCT05032326	PHASE3	UNKNOWN	Long-term Interventional Follow-up Study of Children With Prader-Willi Syndrome Included in the OTBB3 Clinical Trial
NCT05387798	PHASE3	WITHDRAWN	A Phase 3 Extension Study of RAD011 (Cannabidiol Oral Solution) in Patients With Prader-Willi Syndrome
NCT05701774	PHASE3	ACTIVE_NOT_RECRUITING	Open-Label Extension Study of DCCR in Patients With Prader-Willi Syndrome
NCT06144645	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Evaluation of Non-Invasive Vagus Nerve Stimulation for Temper Outbursts in People With PWS
NCT06366464	PHASE3	RECRUITING	A Study of Pitolisant in Patients With Prader-Willi Syndrome
NCT06828861	PHASE3	SUSPENDED	ARD-101 for Treatment of PWS: The Hunger Elimination or Reduction Objective Trial
NCT07197034	PHASE3	SUSPENDED	The Hunger Elimination or Reduction Objective (HERO ) Open -Label Extension (OLE) Trial
NCT07219485	PHASE3	ENROLLING_BY_INVITATION	A Study of Pitolisant in Participants With Prader-Willi Syndrome
NCT02893254	PHASE3	COMPLETED	Efficacy and Safety of IBI303 in Adult Patients With Active Ankylosing Spondylitis
NCT03882918	PHASE3	TERMINATED	An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals With Angelman Syndrome
NCT06415344	PHASE3	ENROLLING_BY_INVITATION	Long-term Extension of GTX-102 in Angelman Syndrome
NCT06617429	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Efficacy and Safety Study of GTX-102 in Pediatric Subjects With Angelman Syndrome (AS)
NCT06914609	PHASE3	RECRUITING	REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome
NCT07605429	PHASE3	NOT_YET_RECRUITING	Phase III Clinical Study of Rugonersen in Angelman Syndrome.
NCT01038570	PHASE2	COMPLETED	Comparative Study Between Prader-Willi Patients Who Take Oxytocin Versus Placebo
NCT01818921	PHASE2	COMPLETED	An Efficacy, Safety, and Pharmacokinetics Study of Beloranib in Obese Subjects With Prader-Willi Syndrome
NCT02311673	PHASE2	COMPLETED	Phase 2 Trial to Evaluate Safety and Efficacy of Setmelanotide (RM-493) in Obese Participants With Prader-Willi Syndrome
NCT02629991	PHASE2	COMPLETED	Oxytocin vs. Placebo for the Treatment Hyperphagia in Children and Adolescents With Prader-Willi Syndrome
NCT02844933	PHASE2	TERMINATED	Cannabidiol Oral Solution for the Treatment of Patients With Prader-Willi Syndrome
NCT02893618	PHASE2	UNKNOWN	A 5 Treatment Period Pharmacokinetic Study Evaluating Dose Proportionality and Food Effects of Diazoxide Choline Controlled-Release Tablet (DCCR)