HERC1

Summary

HERC1 (HECT and RLD domain containing E3 ubiquitin protein ligase family member 1, HGNC:4867) is a protein-coding gene on chromosome 15q22.31, encoding Probable E3 ubiquitin-protein ligase HERC1 (Q15751). Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin.

This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes.

Source: NCBI Gene 8925 — RefSeq curated summary.

At a glance

• Gene–disease (curated): macrocephaly, dysmorphic facies, and psychomotor retardation (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 1,813 total — 26 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 65
• MANE Select transcript: NM_003922

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4867
Approved symbol	HERC1
Name	HECT and RLD domain containing E3 ubiquitin protein ligase family member 1
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	p532, p619
Ensembl gene	ENSG00000103657
Ensembl biotype	protein_coding
OMIM	605109
Entrez	8925

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 6 protein_coding, 6 retained_intron, 3 nonsense_mediated_decay

ENST00000443617, ENST00000558324, ENST00000558532, ENST00000559715, ENST00000559886, ENST00000559996, ENST00000560316, ENST00000560462, ENST00000560519, ENST00000560897, ENST00000560983, ENST00000561348, ENST00000561359, ENST00000561400, ENST00000561436

RefSeq mRNA: 1 — MANE Select: NM_003922 NM_003922

CCDS: CCDS45277

Canonical transcript exons

ENST00000443617 — 78 exons

Exon	Start	End
ENSE00000692891	63672496	63672694
ENSE00000885117	63729497	63729649
ENSE00000931549	63641470	63641643
ENSE00000931557	63652414	63652541
ENSE00000931566	63669538	63669698
ENSE00001034003	63752958	63753085
ENSE00001034004	63749367	63749538
ENSE00001136982	63692411	63692566
ENSE00001289772	63693964	63694157
ENSE00001290065	63734724	63734849
ENSE00001290522	63658544	63658718
ENSE00001291913	63655742	63655955
ENSE00001292694	63727647	63727838
ENSE00001293526	63680537	63680776
ENSE00001294603	63638411	63638536
ENSE00001294718	63642957	63643058
ENSE00001294889	63677845	63678365
ENSE00001295122	63608618	63609266
ENSE00001296241	63666356	63666472
ENSE00001296303	63615768	63615920
ENSE00001297282	63660973	63661025
ENSE00001297462	63698728	63698996
ENSE00001298458	63694774	63694894
ENSE00001300592	63732924	63733145
ENSE00001302617	63622815	63622891
ENSE00001302657	63645483	63645682
ENSE00001302672	63630466	63630635
ENSE00001303170	63690541	63690647
ENSE00001303249	63723182	63723355
ENSE00001304498	63674342	63675117
ENSE00001304506	63638711	63638776
ENSE00001304685	63718574	63718694
ENSE00001306593	63713353	63713665
ENSE00001306814	63664470	63664594
ENSE00001306893	63643404	63643550
ENSE00001307922	63661753	63662021
ENSE00001308073	63706780	63706831
ENSE00001308933	63659736	63659936
ENSE00001309474	63656088	63656358
ENSE00001312330	63616430	63616682
ENSE00001312432	63729236	63729368
ENSE00001312546	63649725	63649925
ENSE00001314283	63686359	63686535
ENSE00001315093	63665919	63666150
ENSE00001315162	63637505	63637643
ENSE00001315739	63680077	63680160
ENSE00001317116	63716302	63716473
ENSE00001320761	63654119	63654324
ENSE00001320845	63694312	63694549
ENSE00001320860	63749647	63749791
ENSE00001323044	63689589	63689699
ENSE00001323636	63648069	63648199
ENSE00001324977	63651253	63651380
ENSE00001325277	63725292	63725513
ENSE00001326451	63640152	63640445
ENSE00001326943	63644992	63645097
ENSE00001327238	63662984	63663204
ENSE00001327313	63712775	63712895
ENSE00001739334	63612251	63612556
ENSE00002566533	63833827	63833948
ENSE00003458352	63625985	63626154
ENSE00003467276	63755229	63755325
ENSE00003483289	63756437	63756748
ENSE00003484327	63623725	63623890
ENSE00003485363	63718783	63718897
ENSE00003517806	63747724	63747858
ENSE00003528804	63764096	63764191
ENSE00003541671	63635961	63636142
ENSE00003543308	63624158	63624327
ENSE00003548122	63634733	63634888
ENSE00003560459	63628677	63628815
ENSE00003564255	63633848	63633970
ENSE00003588587	63774694	63775649
ENSE00003594839	63754505	63754648
ENSE00003601321	63758175	63758369
ENSE00003637442	63746918	63747083
ENSE00003640469	63632709	63632811
ENSE00003786010	63696124	63696339

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.1143 / max 481.2694, expressed in 1811 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150435	31.9179	1809
150437	2.0929	1119
150436	0.6501	388
150434	0.4534	162

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	97.89	gold quality
middle temporal gyrus	UBERON:0002771	97.75	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.62	gold quality
ganglionic eminence	UBERON:0004023	96.88	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.69	gold quality
cerebellar hemisphere	UBERON:0002245	96.59	gold quality
cerebellar cortex	UBERON:0002129	96.57	gold quality
primary visual cortex	UBERON:0002436	96.53	gold quality
prefrontal cortex	UBERON:0000451	96.31	gold quality
calcaneal tendon	UBERON:0003701	96.24	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.21	gold quality
biceps brachii	UBERON:0001507	96.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.15	gold quality
cerebellum	UBERON:0002037	96.14	gold quality
right frontal lobe	UBERON:0002810	95.98	gold quality
granulocyte	CL:0000094	95.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.89	gold quality
frontal cortex	UBERON:0001870	95.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.57	gold quality
neocortex	UBERON:0001950	95.41	gold quality
ventricular zone	UBERON:0003053	95.37	gold quality
trabecular bone tissue	UBERON:0002483	95.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.14	gold quality
sural nerve	UBERON:0015488	95.02	gold quality
tibial nerve	UBERON:0001323	94.95	gold quality
occipital lobe	UBERON:0002021	94.92	gold quality
gastrocnemius	UBERON:0001388	94.79	gold quality
cerebral cortex	UBERON:0000956	94.71	gold quality
muscle of leg	UBERON:0001383	94.68	gold quality
superior frontal gyrus	UBERON:0002661	94.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	2247.04
E-ANND-3	yes	9.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

87 targeting HERC1, 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-6127	100.00	66.76	2188
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6833-3P	100.00	70.63	3197
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-4768-5P	100.00	69.49	2861
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-576-5P	99.84	70.46	2582

Literature-anchored findings (GeneRIF, showing 13)

• physical interaction between the HECT domain of HERC1, a giant protein involved in intracellular membrane traffic, and the M2 isoform of glycolytic enzyme pyruvate kinase (M2-PK) (PMID:12650930)
• HERC1 overexpression does not stimulate protrusion formation in the absence of AlF(4)(-), in conditions where ARNO does, indicating that HERC1 is not acting as an ARF6-GEF, but instead its recruitment takes place downstream of ARF6 activation (PMID:14960311)
• HERC1, through its RLD1 (RCC1-like domain), stimulates GDP release from ARF6 but it inhibits GDP/GTP exchange on ARF6 under conditions where ARNO stimulates it. (PMID:15642342)
• global frequency distributions of 4 single nucleotide polymorphisms in the HERC1 gene; 12 population groups included (PMID:19618402)
• Data show that E3 ubiquitin-protein ligase HERC1 interacts with bcl-2 homologous antagonist-killer protein BAK in HPV5 E6-expressing cells that have been damaged by UV. (PMID:25408501)
• Biallelic sequence variants in a novel gene (HERC1) are linked to a syndromic form of overgrowth and intellectual disability. (PMID:26138117)
• In the light of recent reports of HERC1 mutations in two families with a similar phenotypic presentation, this report reiterates the pathogenic nature and clinical consequences of HERC1 disruption. (PMID:27108999)
• The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling. (PMID:31965002)
• A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism. (PMID:32921582)
• Identification of a quality-control factor that monitors failures during proteasome assembly. (PMID:34446601)
• The Herc1 gene in neurobiology. (PMID:34990797)
• CircHERC1 promotes non-small cell lung cancer cell progression by sequestering FOXO1 in the cytoplasm and regulating the miR-142-3p-HMGB1 axis. (PMID:37932766)
• The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia. (PMID:39093953)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	herc1	ENSDARG00000077901
mus_musculus	Herc1	ENSMUSG00000038664
rattus_norvegicus	Herc1	ENSRNOG00000051671
drosophila_melanogaster	Rcc1	FBGN0002638
drosophila_melanogaster	CG7420	FBGN0031344
caenorhabditis_elegans		WBGENE00004304

Paralogs (9): ALS2 (ENSG00000003393), SERGEF (ENSG00000129158), RCBTB1 (ENSG00000136144), RCBTB2 (ENSG00000136161), RPGR (ENSG00000156313), RCCD1 (ENSG00000166965), RCC2 (ENSG00000179051), RCC1 (ENSG00000180198), RCC1L (ENSG00000274523)

Protein

Protein identifiers

Probable E3 ubiquitin-protein ligase HERC1 — Q15751 (reviewed: Q15751)

Alternative names: HECT domain and RCC1-like domain-containing protein 1, HECT-type E3 ubiquitin transferase HERC1, p532, p619

All UniProt accessions (9): Q15751, H0YK45, H0YK60, H0YKW7, H0YL07, H0YL74, H0YLG2, H0YMH0, H0YNB1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin. Acts as a GEF for Arf and Rab, by exchanging bound GDP for free GTP. Binds phosphatidylinositol 4,5-bisphosphate, which is required for GEF activity. May also act as a E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

Subunit / interactions. Interacts with TSC2; interaction is inhibited by TSC1. Interacts with PKM, ARF1 and ARF6. Forms a ternary complex with clathrin heavy chain (CLTC) and HSPA1A.

Subcellular location. Membrane. Cytoplasm. Cytosol. Golgi apparatus.

Tissue specificity. Widely expressed.

Disease relevance. Macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) [MIM:617011] An autosomal recessive syndrome characterized by large head and somatic overgrowth, intellectual disability, and facial dysmorphism. Seizures, hypotonia and ataxic gait are observed in some patients. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_003913* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR000569	HECT_dom	Domain
IPR001680	WD40_rpt	Repeat
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR035768	SPRY_HERC1	Domain
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR051625	Signaling_Regulatory_Domain	Family
IPR058923	RCC1-like_dom	Domain

Pfam: PF00400, PF00415, PF00622, PF00632, PF25390

UniProt features (143 total): strand 46, repeat 21, sequence variant 15, helix 14, modified residue 14, region of interest 12, compositionally biased region 12, turn 4, domain 2, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4QT6	X-RAY DIFFRACTION	1.64
4O2W	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

No AlphaFold model available for Q15751 — 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): 4811 (glycyl thioester intermediate)

Post-translational modifications (14): 1342, 1406, 1428, 1491, 1512, 1517, 1521, 2422, 2701, 2706, 2710, 2720, 2723, 4857

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 359 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_METENCEPHALON_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_CEREBELLAR_PURKINJE_CELL_LAYER_FORMATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_CEREBELLAR_CORTEX_MORPHOGENESIS, GOBP_NEUROGENESIS, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, SRF_C

GO Biological Process (11): autophagy (GO:0006914), gene expression (GO:0010467), negative regulation of autophagy (GO:0010507), protein ubiquitination (GO:0016567), cerebellar Purkinje cell differentiation (GO:0021702), corpus callosum development (GO:0022038), bone mineralization (GO:0030282), neuron projection development (GO:0031175), bone remodeling (GO:0046849), neuromuscular process controlling balance (GO:0050885), brain development (GO:0007420)

GO Molecular Function (5): guanyl-nucleotide exchange factor activity (GO:0005085), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (4): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
macromolecule biosynthetic process	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
protein modification by small protein conjugation	1
cell differentiation in hindbrain	1
cerebellar Purkinje cell layer formation	1
central nervous system neuron differentiation	1
telencephalon development	1
anatomical structure development	1
ossification	1
biomineral tissue development	1
neuron development	1
plasma membrane bounded cell projection organization	1
tissue remodeling	1
musculoskeletal movement	1
neuromuscular process	1
central nervous system development	1
animal organ development	1
head development	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HERC1	TP53BP2	Q13625	769
HERC1	TP53	P04637	704
HERC1	ARF1	P10947	691
HERC1	CLTCL1	P53675	660
HERC1	S100A8	P05109	573
HERC1	RAP2B	P17964	559
HERC1	MDM2	Q00987	553
HERC1	RABIF	P47224	539
HERC1	CLTC	Q00610	525
HERC1	ARF3	P16587	519
HERC1	RAB3A	P20336	494
HERC1	GEM	P55040	426
HERC1	RAB5A	P20339	411
HERC1	BCL2	P10415	402
HERC1	RSBN1L	Q6PCB5	384

IntAct

151 interactions, top by confidence:

A	B	Type	Score
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
MCM5	MCM3	psi-mi:“MI:0914”(association)	0.850
SNX6	SNX2	psi-mi:“MI:0914”(association)	0.800
ATAT1	YWHAQ	psi-mi:“MI:0914”(association)	0.730
NEUROG3	GXYLT2	psi-mi:“MI:0914”(association)	0.640
rep	ATE1	psi-mi:“MI:0914”(association)	0.640
RAB15	RAP1GDS1	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
AKT3	HSP90AA1	psi-mi:“MI:0914”(association)	0.560
GCNT3	BCKDK	psi-mi:“MI:0914”(association)	0.530
TFDP3	E2F3	psi-mi:“MI:0914”(association)	0.530
ZNF223	PPM1G	psi-mi:“MI:0914”(association)	0.530
ZNF563	LRP4	psi-mi:“MI:0914”(association)	0.530
VPS36	UBB	psi-mi:“MI:0914”(association)	0.530
ECHS1	DBT	psi-mi:“MI:0914”(association)	0.530
TIGD6	MTHFR	psi-mi:“MI:0914”(association)	0.530
ZNF571	HERC1	psi-mi:“MI:0914”(association)	0.530
TRPC4AP	SMCHD1	psi-mi:“MI:0914”(association)	0.530
ZNF223	CENPB	psi-mi:“MI:0914”(association)	0.530
IQGAP3	PEX19	psi-mi:“MI:0914”(association)	0.530

BioGRID (210): HERC1 (Co-localization), BAK1 (Protein-peptide), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), HERC1 (Affinity Capture-RNA), HERC1 (Affinity Capture-MS)

ESM2 similar proteins: A0JM49, A2AKG8, C5J7W8, E1C2Z0, E7FGT5, E9Q368, E9Q555, F6S215, O15050, O43149, O60287, P42859, P51111, P51112, P53995, P59438, Q13315, Q13395, Q15751, Q20CR4, Q3TCV3, Q3TQQ9, Q3TUL7, Q3UHA3, Q4TVR5, Q4VSN3, Q4VSN4, Q4VSN5, Q571H0, Q5EB20, Q5SSH7, Q5VW36, Q5XI94, Q62388, Q69YN4, Q6DRL4, Q6NU51, Q6NV72, Q6PQD5, Q6TNU3

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

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	HERC1	ubiquitination
HERC1	“down-regulates quantity”	PSMC5	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1813 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	23
Uncertain significance	842
Likely benign	626
Benign	182

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073073	NC_000015.9:g.(?63941924)(63944740_?)del	Pathogenic
1074278	NM_003922.4(HERC1):c.316C>T (p.Arg106Ter)	Pathogenic
188045	NM_003922.4(HERC1):c.9748C>T (p.Arg3250Ter)	Pathogenic
1972510	NM_003922.4(HERC1):c.205del (p.Ser69fs)	Pathogenic
1986254	NM_003922.4(HERC1):c.7702C>T (p.Arg2568Ter)	Pathogenic
2230986	NM_003922.4(HERC1):c.5164C>T (p.Gln1722Ter)	Pathogenic
2293157	NM_003922.4(HERC1):c.7771C>T (p.Arg2591Ter)	Pathogenic
243010	NM_003922.4(HERC1):c.2625G>A (p.Trp875Ter)	Pathogenic
243011	NM_003922.4(HERC1):c.13559G>A (p.Gly4520Glu)	Pathogenic
2577836	NM_003922.4(HERC1):c.4396C>T (p.Arg1466Ter)	Pathogenic
2749164	NM_003922.4(HERC1):c.13683_13684dup (p.Asp4562fs)	Pathogenic
2821159	NM_003922.4(HERC1):c.11062del (p.Gln3688fs)	Pathogenic
3069015	NM_003922.4(HERC1):c.11160G>A (p.Trp3720Ter)	Pathogenic
3251447	NM_003922.4(HERC1):c.8504del (p.Gly2835fs)	Pathogenic
3613042	NM_003922.4(HERC1):c.9667C>T (p.Arg3223Ter)	Pathogenic
3648035	NM_003922.4(HERC1):c.10168C>T (p.Gln3390Ter)	Pathogenic
3649929	NM_003922.4(HERC1):c.11897dup (p.Met3967fs)	Pathogenic
3669889	NM_003922.4(HERC1):c.4237C>T (p.Arg1413Ter)	Pathogenic
3684043	NM_003922.4(HERC1):c.11876del (p.Pro3959fs)	Pathogenic
3690618	NM_003922.4(HERC1):c.14341C>T (p.Arg4781Ter)	Pathogenic
4082353	NM_003922.4(HERC1):c.1168C>T (p.Gln390Ter)	Pathogenic
4531508	NM_003922.4(HERC1):c.12728dup (p.Val4244fs)	Pathogenic
4767099	NM_003922.4(HERC1):c.3619C>T (p.Gln1207Ter)	Pathogenic
853776	NM_003922.4(HERC1):c.1183C>T (p.Gln395Ter)	Pathogenic
984952	NM_003922.4(HERC1):c.14072G>C (p.Arg4691Pro)	Pathogenic
985585	NM_003922.4(HERC1):c.681del (p.Gly231fs)	Pathogenic
1067092	NM_003922.4(HERC1):c.12966+2T>G	Likely pathogenic
1201996	NM_003922.4(HERC1):c.4273C>T (p.Arg1425Ter)	Likely pathogenic
1495664	NM_003922.4(HERC1):c.7071-63_7400del	Likely pathogenic
1690832	NM_003922.4(HERC1):c.9920C>G (p.Ser3307Ter)	Likely pathogenic

SpliceAI

14078 predictions. Top by Δscore:

Variant	Effect	Δscore
15:63612247:TTAC:T	donor_loss	1.0000
15:63612248:TA:T	donor_loss	1.0000
15:63612249:A:AC	donor_gain	1.0000
15:63612249:A:AT	donor_loss	1.0000
15:63612249:AC:A	donor_gain	1.0000
15:63612250:C:CC	donor_gain	1.0000
15:63612250:C:CG	donor_loss	1.0000
15:63612250:CC:C	donor_gain	1.0000
15:63615764:TCAC:T	donor_loss	1.0000
15:63615765:CA:C	donor_loss	1.0000
15:63615766:ACCT:A	donor_loss	1.0000
15:63615767:C:CA	donor_loss	1.0000
15:63615767:CCTGT:C	donor_gain	1.0000
15:63615916:ATCAT:A	acceptor_gain	1.0000
15:63615917:TCAT:T	acceptor_gain	1.0000
15:63615918:CAT:C	acceptor_gain	1.0000
15:63615918:CATC:C	acceptor_gain	1.0000
15:63615919:AT:A	acceptor_gain	1.0000
15:63615919:ATC:A	acceptor_loss	1.0000
15:63615920:TCTA:T	acceptor_loss	1.0000
15:63615921:C:CC	acceptor_gain	1.0000
15:63615921:C:CG	acceptor_loss	1.0000
15:63615928:C:CT	acceptor_gain	1.0000
15:63616425:TTTA:T	donor_loss	1.0000
15:63616426:TTA:T	donor_loss	1.0000
15:63616427:TAC:T	donor_loss	1.0000
15:63616429:C:CG	donor_loss	1.0000
15:63616429:CCT:C	donor_gain	1.0000
15:63616443:T:A	donor_gain	1.0000
15:63622890:TC:T	acceptor_gain	1.0000

AlphaMissense

31591 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:63609127:A:G	L4847P	1.000
15:63609129:C:A	M4846I	1.000
15:63609129:C:G	M4846I	1.000
15:63609129:C:T	M4846I	1.000
15:63609130:A:G	M4846T	1.000
15:63609134:A:G	Y4845H	1.000
15:63609139:T:A	D4843V	1.000
15:63609139:T:C	D4843G	1.000
15:63609139:T:G	D4843A	1.000
15:63609140:C:A	D4843Y	1.000
15:63609140:C:G	D4843H	1.000
15:63609145:T:A	D4841V	1.000
15:63609145:T:C	D4841G	1.000
15:63609145:T:G	D4841A	1.000
15:63609146:C:G	D4841H	1.000
15:63609148:A:C	I4840S	1.000
15:63609148:A:T	I4840N	1.000
15:63609156:G:C	C4837W	1.000
15:63609157:C:T	C4837Y	1.000
15:63609158:A:G	C4837R	1.000
15:63609169:G:T	A4833D	1.000
15:63609170:C:G	A4833P	1.000
15:63609178:A:G	L4830P	1.000
15:63609209:A:C	Y4820D	1.000
15:63609217:A:G	L4817P	1.000
15:63609219:C:A	R4816S	1.000
15:63609219:C:G	R4816S	1.000
15:63609220:C:A	R4816M	1.000
15:63609220:C:G	R4816T	1.000
15:63609223:A:C	L4815R	1.000

dbSNP variants (sampled 300 via entrez): RS1000021799 (15:63647972 T>C,G), RS1000029950 (15:63812349 C>A,G,T), RS1000031713 (15:63642494 C>A,G,T), RS1000055557 (15:63818491 C>T), RS1000062066 (15:63829949 A>G), RS1000065111 (15:63676219 C>T), RS1000065461 (15:63817461 T>C), RS1000079081 (15:63679174 C>T), RS1000080471 (15:63811282 T>C), RS1000092518 (15:63771311 T>A), RS1000092542 (15:63770957 G>C), RS1000094607 (15:63609561 C>T), RS1000120949 (15:63759470 A>ATT), RS1000151693 (15:63783359 A>T), RS1000154011 (15:63614062 G>C)

Disease associations

OMIM: gene MIM:605109 | disease phenotypes: MIM:617011

GenCC curated gene-disease

Disease	Classification	Inheritance
macrocephaly, dysmorphic facies, and psychomotor retardation	Definitive	Autosomal recessive
megalencephaly-severe kyphoscoliosis-overgrowth syndrome	Supportive	Autosomal recessive

Mondo (6): macrocephaly, dysmorphic facies, and psychomotor retardation (MONDO:0014863), neurodevelopmental disorder (MONDO:0700092), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), premature menopause (MONDO:0001119), intellectual disability (MONDO:0001071), megalencephaly-severe kyphoscoliosis-overgrowth syndrome (MONDO:0018710)

Orphanet (3): Megalencephaly-severe kyphoscoliosis-overgrowth syndrome (Orphanet:457359), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000098	Tall stature
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000297	Facial hypotonia
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000472	Long neck
HP:0000494	Downslanted palpebral fissures
HP:0000520	Proptosis
HP:0000582	Upslanted palpebral fissure
HP:0000586	Shallow orbits
HP:0001166	Arachnodactyly
HP:0001176	Large hands
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001321	Cerebellar hypoplasia
HP:0001334	Communicating hydrocephalus

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001199_7	Iris characteristics	1.000000e-06
GCST004619_99	Reticulocyte fraction of red cells	9.000000e-11
GCST005163_2	Glucagon levels in response to oral glucose tolerance test (120 minutes)	9.000000e-06
GCST006414_26	Atrial fibrillation	5.000000e-08
GCST007656_8	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	1.000000e-12
GCST009144_20	Disease progression in age-related macular degeneration (adjusted for baseline)	5.000000e-08
GCST009144_7	Disease progression in age-related macular degeneration (adjusted for baseline)	5.000000e-08
GCST010241_201	Apolipoprotein A1 levels	9.000000e-10
GCST90020024_493	A body shape index	4.000000e-08
GCST90020025_146	Waist-to-hip ratio adjusted for BMI	6.000000e-09
GCST90020027_644	Waist-hip index	3.000000e-09
GCST90020029_205	Waist circumference adjusted for body mass index	2.000000e-10

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0007986	reticulocyte count
EFO:0004307	glucose tolerance test
EFO:0008463	glucagon measurement
EFO:0008336	disease progression measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases mutagenesis, affects methylation	5
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
coumarin	affects phosphorylation	1
aluminum fluoride	affects localization	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	decreases expression	1
Caffeine	affects phosphorylation	1
Coumestrol	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Hydrogen Peroxide	increases expression	1
Methotrexate	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Lactic Acid	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XP51	HAP1 HERC1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice