HACE1

Summary

HACE1 (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1, HGNC:21033) is a protein-coding gene on chromosome 6q16.3, encoding E3 ubiquitin-protein ligase HACE1 (Q8IYU2). E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases.

This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm’s tumor.

Source: NCBI Gene 57531 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spastic paraplegia-severe developmental delay-epilepsy syndrome (Definitive, GenCC)
• GWAS associations: 25
• Clinical variants (ClinVar): 357 total — 22 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 83
• MANE Select transcript: NM_020771

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21033
Approved symbol	HACE1
Name	HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1
Location	6q16.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1320
Ensembl gene	ENSG00000085382
Ensembl biotype	protein_coding
OMIM	610876
Entrez	57531

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000262903, ENST00000369125, ENST00000369127, ENST00000416605, ENST00000517424, ENST00000517995, ENST00000518228, ENST00000518402, ENST00000518503, ENST00000519645, ENST00000521962, ENST00000524020, ENST00000851407, ENST00000851408, ENST00000851409, ENST00000851410, ENST00000851411, ENST00000914226, ENST00000914227, ENST00000950219, ENST00000950220, ENST00000950221, ENST00000950222

RefSeq mRNA: 11 — MANE Select: NM_020771 NM_001321080, NM_001321083, NM_001321084, NM_001350554, NM_001350555, NM_001350556, NM_001350557, NM_001350558, NM_001350559, NM_001350560, NM_020771

CCDS: CCDS5050

Canonical transcript exons

ENST00000262903 — 24 exons

Exon	Start	End
ENSE00001084739	104728094	104729764
ENSE00001295098	104833042	104833173
ENSE00001298139	104859567	104859919
ENSE00003465217	104771925	104772074
ENSE00003502109	104811311	104811393
ENSE00003507581	104771193	104771389
ENSE00003508669	104744512	104744610
ENSE00003518516	104750341	104750472
ENSE00003523795	104784417	104784485
ENSE00003524065	104777013	104777110
ENSE00003553216	104796929	104797025
ENSE00003570222	104730303	104730416
ENSE00003573532	104777206	104777317
ENSE00003605896	104843223	104843298
ENSE00003606363	104744160	104744230
ENSE00003607821	104784086	104784173
ENSE00003618499	104849142	104849246
ENSE00003632611	104791504	104791654
ENSE00003634554	104784985	104785319
ENSE00003637869	104776741	104776828
ENSE00003651042	104795579	104795685
ENSE00003675773	104796655	104796756
ENSE00003679463	104852317	104852371
ENSE00003686140	104850907	104850996

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 93.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.8209 / max 155.8396, expressed in 1635 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74863	6.5786	1623
74862	0.2080	69
74860	0.0292	13
74861	0.0051	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.74	gold quality
oocyte	CL:0000023	93.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.29	gold quality
endothelial cell	CL:0000115	91.00	gold quality
placenta	UBERON:0001987	90.88	gold quality
primary visual cortex	UBERON:0002436	88.38	gold quality
cerebellar hemisphere	UBERON:0002245	88.04	gold quality
epithelial cell of pancreas	CL:0000083	87.95	gold quality
cerebellar cortex	UBERON:0002129	87.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.88	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.75	gold quality
ventricular zone	UBERON:0003053	87.59	gold quality
cerebellum	UBERON:0002037	87.58	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.50	gold quality
occipital lobe	UBERON:0002021	86.72	gold quality
prefrontal cortex	UBERON:0000451	86.18	gold quality
esophagus squamous epithelium	UBERON:0006920	85.99	gold quality
frontal cortex	UBERON:0001870	85.69	gold quality
frontal lobe	UBERON:0016525	85.69	gold quality
neocortex	UBERON:0001950	85.66	gold quality
pigmented layer of retina	UBERON:0001782	85.58	gold quality
right frontal lobe	UBERON:0002810	85.52	gold quality
cerebral cortex	UBERON:0000956	85.46	gold quality
superior frontal gyrus	UBERON:0002661	85.35	gold quality
anterior cingulate cortex	UBERON:0009835	85.30	gold quality
ganglionic eminence	UBERON:0004023	85.19	gold quality
caudate nucleus	UBERON:0001873	85.03	gold quality
stromal cell of endometrium	CL:0002255	84.99	gold quality
calcaneal tendon	UBERON:0003701	84.82	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	7.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

125 targeting HACE1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493

Literature-anchored findings (GeneRIF, showing 40)

• Hace1 as a novel ubiquitin-protein ligase with very low expression Wilms’ tumors; hypermethylation of two upstream CpG islands correlates with low HACE1 expression in tumor samples. (PMID:15254018)
• HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers. (PMID:17694067)
• Aberrant methylation of the HACE1 gene was detected in 9 out of the 32 (28%) primary colon carcinomas. (PMID:18630515)
• Aberrant methylation of the HACE1 gene is associated with gastric carcinoma. (PMID:19528486)
• Deregulation of the tumor suppressor HACE1 is associated with natural killer/T-cell lymphoma, nasal type. (PMID:19965620)
• The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility, such as mutations in gene HACE1. (PMID:21326284)
• The HACE1 expression increases the ubiquitylation of Rac1, when the GTPase is activated by point mutations or by the GEF-domain of Dbl. (PMID:22036506)
• HACE1 is an antagonist of cell migration through its ability to degrade active Rac1. (PMID:22614015)
• common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression. (PMID:22941191)
• HACE1 is tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell lymphomagenesis. (PMID:23142381)
• All stages of HCCs presented HACE1 methylation, indicating that the HACE1 gene has been methylated from the early stages of HCCs. (PMID:23732777)
• Ubiquitylation and activation of RAB11a is promoted by a beta2 adrenergic receptor-HACE1 complex. (PMID:24190883)
• HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. (PMID:24516159)
• HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells. (PMID:25026213)
• contrary to previous report, overexpression of HACE1 by transduction of recombinant protein did not affect proliferation or survival of NKTCL cell lines. We therefore conclude that HACE1 is not directly involved in NKTCL pathophysiology (PMID:25203537)
• supports a critical role for HACE1 in breast cancer progression and identifies patients that may benefit from Rac-targeted therapies (PMID:25659579)
• HACE1 as a specific E3 ligase that polyubiquitinates YB-1 through non-canonical K27 linked ubiquitin chains. (PMID:26343856)
• Biallelic loss-of-function mutations in HACE1 are associated with an autosomal recessive neurodevelopmental syndrome. (PMID:26424145)
• HACE1 can act as a haploinsufficient tumor suppressor gene in most B-cell lymphomas and can be downregulated by deacetylation of its promoter region chromatin (PMID:27107267)
• Mechanistic studies showed that HACE1 exerts its inhibitory role on virus-induced signaling by disrupting the MAVS-TRAF3 complex. (PMID:27213432)
• Hepatocellular carcinoma patients with low HACE1 expression levels exhibited poorer overall survival and HACE1 was found to be an independent prognostic factor for survival. (PMID:27805249)
• A functional interplay between HACE1 and Rac1 in cancer, is reported. (PMID:28317937)
• 3-deazaneplanocin A treatment increased HACE1 gene expression which was further increased by the addition of trichostatine A (TSA), a promising therapeutic compound for the treatment of human B-Lymphoma (PMID:28651105)
• Results indicated that HACE1 rs9404576 polymorphism may be associated with Wilms’ tumor susceptibility in the Chinese population. (PMID:29243987)
• Results identified HACE1 Ser-385 as a pivotal amino acid residue that is phosphorylated in response to CNF1 or VEGF treatments and that expression of activated Rac1 is sufficient to induce HACE1 phosphorylation and controlling its oligomerization state. (PMID:29362425)
• HACE1 promoted the K27 ubiquitination of fibronectin and regulated its secretion. Secreted fibronectin regulated ITGAV and ITGB1 expression, as well as melanoma cell adhesion and migration. (PMID:29515254)
• our studies unveiled a suppressive role of HACE1 in tumor growth and migration of gastric cancer, and it might help to provide novel insights into the blockage of tumorigenesis and malignant process of early stage of gastric cancer. (PMID:29673126)
• HACE1-YAP1 axis had an important part in the Colorectal cancer development and progression. (PMID:30362561)
• Ectopic expression of HACE1 markedly inhibited anchorage-independent growth and cell motility of HACE1 osteosarcoma cell lines, HACE1 overexpression blocked osteosarcoma xenograft growth and dramatically reduced pulmonary metastases. These findings point to a potential tumor suppressor function for HACE1 in osteosarcoma. (PMID:30622235)
• FIH interacts with the ankyrin repeat domain of HACE1.HACE1 is hydroxylated at asparagine 191 by FIH.FIH-dependent hydroxylation of HACE1 inhibits HACE1 ability to ubiquitinate Rac1.HACE1 expression inversely correlates with breast cancer progression. (PMID:30659265)
• The present study demonstrates that KSHV infection induces the E3 ligase HACE1 protein to regulate KSHV-induced oxidative stress by promoting the activation of Nrf2 and nuclear translocation. (PMID:30787155)
• Loss of the Tumor Suppressor HACE1 Contributes to Cancer Progression. (PMID:30827236)
• meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes. (PMID:32616021)
• Ubiquitin-independent proteasomal degradation of Spindlin-1 by the E3 ligase HACE1 contributes to cell-cell adhesion. (PMID:33421097)
• Correlations of HACE1 expression with pathological stages, CT features and prognosis of hepatocellular carcinoma patients. (PMID:33455098)
• HACE1 blocks HIF1alpha accumulation under hypoxia in a RAC1 dependent manner. (PMID:33603169)
• HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson’s disease models. (PMID:34593974)
• HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells. (PMID:34815381)
• Structural Basis for the Enzymatic Activity of the HACE1 HECT-Type E3 Ligase Through N-Terminal Helix Dimerization. (PMID:37537642)
• HACE1 expression in heart failure patients might promote mitochondrial oxidative stress and ferroptosis by targeting NRF2. (PMID:38070140)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hace1	ENSDARG00000062280
mus_musculus	Hace1	ENSMUSG00000038822
rattus_norvegicus	Hace1	ENSRNOG00000000327

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), 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 HACE1 — Q8IYU2 (reviewed: Q8IYU2)

Alternative names: HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase 1, HECT-type E3 ubiquitin transferase HACE1

All UniProt accessions (8): Q8IYU2, E3W983, E5RFX0, E5RHI1, H0YAU8, H0YBH3, H0YC01, H0YC48

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases. Acts as a regulator of Golgi membrane dynamics during the cell cycle: recruited to Golgi membrane by Rab proteins and regulates postmitotic Golgi membrane fusion. Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after cell division. Specifically binds GTP-bound RAC1, mediating ubiquitination and subsequent degradation of active RAC1, thereby playing a role in host defense against pathogens. May also act as a transcription regulator via its interaction with RARB.

Subunit / interactions. Homodimer. The homodimer is autoinhibited and stabilized by its N-terminal helix. Interacts with RAB1 (RAB1A, RAB1B or RAB1C), RAB4 (RAB4A or RAB4B) and RAB11 (RAB11A or RAB11B); in a GTP-dependent manner. Interacts with the 26S proteasomal complex through the 20S core proteasomal subunit. Interacts with RARB.

Subcellular location. Golgi apparatus. Golgi stack membrane. Cytoplasm. Endoplasmic reticulum.

Tissue specificity. Expressed in multiple tissues including heart, brain and kidney.

Post-translational modifications. Autoubiquitinated.

Disease relevance. Defects in HACE1 are a cause of Wilms tumor (WT). WT is a pediatric malignancy of kidney and one of the most common solid cancers in childhood. HACE1 is epigenetically down-regulated in sporadic Wilms tumor. Moreover, a t(5;6)(q21;q21) translocation that truncates HACE1 has been found in a child with bilateral, young-onset Wilms tumor. Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) [MIM:616756] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPPRS is an autosomal recessive neurodevelopmental disorder manifesting in infancy. Affected individuals show hypotonia and psychomotor retardation. Most develop seizures. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Sterically autoinhibited in its dimeric state.

Domain organisation. The N-terminal lobe of the HECT domain is important for interaction with E2 ubiquitin-conjugating enzymes. The ANK repeats ANK 3, ANK 4 and ANK 5 are important for recognizing the RAC1 substrate.

Induction. Down-regulated in sporadic Wilms tumor.

Pathway. Protein modification; protein ubiquitination.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8IYU2-1	1	yes
Q8IYU2-2	2
Q8IYU2-3	3
Q8IYU2-4	4

RefSeq proteins (11): NP_001308009, NP_001308012, NP_001308013, NP_001337483, NP_001337484, NP_001337485, NP_001337486, NP_001337487, NP_001337488, NP_001337489, NP_065822* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000569	HECT_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR050409	E3_ubiq-protein_ligase	Family

Pfam: PF00632, PF12796, PF13637

UniProt features (42 total): mutagenesis site 19, repeat 7, splice variant 4, sequence conflict 4, sequence variant 3, region of interest 2, chain 1, active site 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8H8X	ELECTRON MICROSCOPY	3.92
8Q0N	ELECTRON MICROSCOPY	4.2
8HAE	ELECTRON MICROSCOPY	4.55
8PWL	ELECTRON MICROSCOPY	4.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYU2-F1	83.99	0.54

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): 876 (glycyl thioester intermediate)

Mutagenesis-validated functional residues (19):

Position	Phenotype
8	exists as a mixture of monomer and dimer; promotes autoubiquitination and ubiquitination of rac1.
11	exists as a mixture of monomer and dimer; promotes autoubiquitination and ubiquitination of rac1.
11	monomeric; promotes autoubiquitination and ubiquitination of rac1.
14	monomeric; promotes autoubiquitination and ubiquitination of rac1.
15	monomeric; promotes autoubiquitination and ubiquitination of rac1.
20	monomeric; promotes autoubiquitination and ubiquitination of rac1.
140	promotes ubiquitination of rac1.
173	impairs ubiquitination of rac1.
174	impairs ubiquitination of rac1.
175	impairs ubiquitination of rac1.
204	impairs ubiquitination of rac1.
332	promotes ubiquitination of rac1.
353	promotes ubiquitination of rac1.
694	monomeric; loss of e3 ubiquitin ligase activity.
704	dimeric; loss of e3 ubiquitin ligase activity.
706	monomeric; loss of e3 ubiquitin ligase activity.
876	loss of e3 ubiquitin ligase activity.
906	abolishes ubiquitination of rac1.
907–909	abolishes ubiquitination of rac1.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9958825	Activation of STAT3 by cadherin engagement

MSigDB gene sets: 311 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MEMBRANE_FUSION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOMF_GTPASE_BINDING, BILD_E2F3_ONCOGENIC_SIGNATURE, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_MEMBRANE_ORGANIZATION

GO Biological Process (7): ubiquitin-dependent protein catabolic process (GO:0006511), Golgi organization (GO:0007030), protein ubiquitination (GO:0016567), Rac protein signal transduction (GO:0016601), regulation of cell migration (GO:0030334), membrane fusion (GO:0061025), protein K48-linked ubiquitination (GO:0070936)

GO Molecular Function (5): ubiquitin-protein transferase activity (GO:0004842), small GTPase binding (GO:0031267), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (9): Golgi membrane (GO:0000139), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), nuclear body (GO:0016604), Golgi cisterna membrane (GO:0032580), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Adherens junctions interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
cytoplasm	2
endomembrane system	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
organelle organization	1
endomembrane system organization	1
protein modification by small protein conjugation	1
small GTPase-mediated signal transduction	1
cell migration	1
regulation of cell motility	1
membrane organization	1
protein polyubiquitination	1
ubiquitin-like protein transferase activity	1
GTPase binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1
organelle membrane	1
Golgi cisterna	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1211 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HACE1	ELAPOR1	Q6UXG2	942
HACE1	CNTN2	P78432	457
HACE1	HTT	P42858	444
HACE1	RAB1A	P11476	414
HACE1	RAB8A	P24407	413
HACE1	OPTN	Q96CV9	354
HACE1	MLF1	P58340	347
HACE1	VCPIP1	Q96JH7	337
HACE1	ANK3	Q12955	305
HACE1	ANK2	Q01484	304
HACE1	ANK1	P16157	303
HACE1	SMG9	Q9H0W8	297
HACE1	VRK1	Q99986	276
HACE1	ZNF598	Q86UK7	275
HACE1	BAZ1A	Q9NRL2	270

IntAct

33 interactions, top by confidence:

A	B	Type	Score
HACE1	OPTN	psi-mi:“MI:0915”(physical association)	0.690
OPTN	HACE1	psi-mi:“MI:0915”(physical association)	0.690
OPTN	HACE1	psi-mi:“MI:0403”(colocalization)	0.690
HACE1	RAC1	psi-mi:“MI:0915”(physical association)	0.620
HACE1	RAC1	psi-mi:“MI:0407”(direct interaction)	0.620
HACE1	RAC1	psi-mi:“MI:0403”(colocalization)	0.620
RAB4A	HACE1	psi-mi:“MI:0915”(physical association)	0.560
OPTN	SQSTM1	psi-mi:“MI:0914”(association)	0.560
IRF7	AIP	psi-mi:“MI:0914”(association)	0.500
HACE1		psi-mi:“MI:0220”(ubiquitination reaction)	0.440
Rac1	HACE1	psi-mi:“MI:0915”(physical association)	0.400
HACE1	POTEF	psi-mi:“MI:0915”(physical association)	0.400
PLXNA2	HACE1	psi-mi:“MI:0915”(physical association)	0.370
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (117): HACE1 (Affinity Capture-Western), YBX1 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), HACE1 (Biochemical Activity), UBE2L3 (Reconstituted Complex), HACE1 (Affinity Capture-Western), SNTG2 (Biochemical Activity), UBE2L3 (Reconstituted Complex), HACE1 (Reconstituted Complex), HACE1 (Affinity Capture-MS), HACE1 (Reconstituted Complex), HACE1 (Reconstituted Complex), HACE1 (Biochemical Activity), HACE1 (Biochemical Activity), RAC1 (Biochemical Activity)

ESM2 similar proteins: A0A0G2K344, A0JM23, D3ZBM7, E1C656, F1M386, F1N6G5, F1PBJ0, F8W2M1, O02697, O08759, O14830, O35385, P0CI65, P32871, P42336, P42337, P42338, P48736, Q05086, Q15034, Q28BK1, Q3U0D9, Q3UMR0, Q5GLZ8, Q5PQN1, Q5RD78, Q5REW9, Q5U5R9, Q6AZT7, Q6DCL5, Q6PAV2, Q7TNH6, Q7Z494, Q8BTI9, Q8CDU6, Q8CHG5, Q8CHG7, Q8IVU3, Q8IYU2, Q8K4M9

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

6 interactions.

A	Effect	B	Mechanism
PAK1	“down-regulates activity”	HACE1	phosphorylation
HACE1	“down-regulates quantity by destabilization”	RAC1	ubiquitination
Ub:E2	“up-regulates activity”	HACE1	ubiquitination
HACE1	“down-regulates quantity by destabilization”	CCND1	ubiquitination
HACE1	“down-regulates quantity by destabilization”	OPTN	ubiquitination
HACE1	“down-regulates quantity”	RAC1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	16
Uncertain significance	127
Likely benign	143
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1188822	NM_020771.4(HACE1):c.239G>A (p.Cys80Tyr)	Pathogenic
1460183	NC_000006.11:g.(?105177537)(105307517_?)del	Pathogenic
1700211	NM_020771.4(HACE1):c.355G>T (p.Glu119Ter)	Pathogenic
1708240	NM_020771.4(HACE1):c.152C>G (p.Ser51Ter)	Pathogenic
2039047	NM_020771.4(HACE1):c.1014dup (p.Ser339fs)	Pathogenic
221289	NM_020771.4(HACE1):c.655C>T (p.Arg219Ter)	Pathogenic
221290	NM_020771.4(HACE1):c.2242C>T (p.Arg748Ter)	Pathogenic
221291	NC_000006.12:g.104771387TACCTAAAAA[3]	Pathogenic
221293	NM_020771.4(HACE1):c.1852_1853del (p.Gln618fs)	Pathogenic
221294	NM_020771.4(HACE1):c.454C>T (p.Gln152Ter)	Pathogenic
221295	NM_020771.4(HACE1):c.805C>T (p.Arg269Ter)	Pathogenic
221296	NM_020771.4(HACE1):c.240C>A (p.Cys80Ter)	Pathogenic
2426590	NC_000006.11:g.(?105239359)(105239549_?)del	Pathogenic
3068745	NM_020771.4(HACE1):c.859C>T (p.Gln287Ter)	Pathogenic
3629514	NC_000006.11:g.(?105175968)(105307795_?)del	Pathogenic
3775928	NM_020771.4(HACE1):c.1225G>T (p.Glu409Ter)	Pathogenic
4689681	NC_000006.11:g.(?105175968)(105259269_105280916)del	Pathogenic
4734587	NM_020771.4(HACE1):c.177T>G (p.Tyr59Ter)	Pathogenic
4814229	NM_020771.4(HACE1):c.1589G>A (p.Trp530Ter)	Pathogenic
4847657	NM_020771.4(HACE1):c.2313_2316del (p.Leu772fs)	Pathogenic
548455	NM_020771.4(HACE1):c.1396C>T (p.Gln466Ter)	Pathogenic
802254	NM_020771.4(HACE1):c.1712C>A (p.Ser571Ter)	Pathogenic
1324524	NM_020771.4(HACE1):c.1443C>A (p.Cys481Ter)	Likely pathogenic
2629857	NM_020771.4(HACE1):c.1049_1050insC (p.Lys350fs)	Likely pathogenic
2877614	NM_020771.4(HACE1):c.2014+1G>A	Likely pathogenic
2982269	NM_020771.4(HACE1):c.2212-1G>A	Likely pathogenic
3242256	NM_020771.4(HACE1):c.1759del (p.His587fs)	Likely pathogenic
3592858	NM_020771.4(HACE1):c.1865-2A>G	Likely pathogenic
3899864	NM_020771.4(HACE1):c.1506dup (p.His503fs)	Likely pathogenic
4081441	NM_020771.4(HACE1):c.714+1G>A	Likely pathogenic

SpliceAI

3998 predictions. Top by Δscore:

Variant	Effect	Δscore
6:104729765:C:CC	acceptor_gain	1.0000
6:104744228:CCA:C	acceptor_gain	1.0000
6:104744229:CA:C	acceptor_gain	1.0000
6:104744229:CAC:C	acceptor_gain	1.0000
6:104744231:C:CC	acceptor_gain	1.0000
6:104744509:TACC:T	donor_loss	1.0000
6:104744510:ACCT:A	donor_loss	1.0000
6:104744511:CCTGA:C	donor_loss	1.0000
6:104744608:CTC:C	acceptor_gain	1.0000
6:104744610:CCT:C	acceptor_gain	1.0000
6:104744611:C:A	acceptor_loss	1.0000
6:104744611:C:CC	acceptor_gain	1.0000
6:104744611:C:T	acceptor_gain	1.0000
6:104744612:T:C	acceptor_gain	1.0000
6:104744612:T:G	acceptor_loss	1.0000
6:104744612:T:TC	acceptor_gain	1.0000
6:104750335:CCTTA:C	donor_loss	1.0000
6:104750336:CTT:C	donor_loss	1.0000
6:104750337:TTA:T	donor_loss	1.0000
6:104750338:TAC:T	donor_loss	1.0000
6:104750339:A:AA	donor_loss	1.0000
6:104750340:C:CT	donor_loss	1.0000
6:104750473:C:CC	acceptor_gain	1.0000
6:104771185:ATACT:A	donor_loss	1.0000
6:104771187:ACT:A	donor_loss	1.0000
6:104771189:TCACT:T	donor_loss	1.0000
6:104771190:CACT:C	donor_loss	1.0000
6:104771191:A:AC	donor_gain	1.0000
6:104771192:C:CC	donor_gain	1.0000
6:104771192:CTTT:C	donor_gain	1.0000

AlphaMissense

6033 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:104729753:A:G	L880P	1.000
6:104730304:A:G	C876R	1.000
6:104730308:G:C	S874R	1.000
6:104730308:G:T	S874R	1.000
6:104730310:T:G	S874R	1.000
6:104730318:G:C	P871R	1.000
6:104730318:G:T	P871Q	1.000
6:104744163:C:T	G837D	1.000
6:104744164:C:G	G837R	1.000
6:104744568:A:G	W796R	1.000
6:104744568:A:T	W796R	1.000
6:104771327:A:G	W693R	1.000
6:104771327:A:T	W693R	1.000
6:104772006:C:A	G645W	1.000
6:104776807:A:G	W600R	1.000
6:104776807:A:T	W600R	1.000
6:104777091:G:C	S566R	1.000
6:104777091:G:T	S566R	1.000
6:104777093:T:G	S566R	1.000
6:104777296:A:G	W530R	1.000
6:104777296:A:T	W530R	1.000
6:104784107:G:C	F515L	1.000
6:104784107:G:T	F515L	1.000
6:104784109:A:G	F515L	1.000
6:104784456:A:T	V480D	1.000
6:104784468:A:G	F476S	1.000
6:104785282:A:G	L371P	1.000
6:104785286:A:G	W370R	1.000
6:104785286:A:T	W370R	1.000
6:104785304:A:G	W364R	1.000

dbSNP variants (sampled 300 via entrez): RS1000004834 (6:104848024 G>T), RS1000023916 (6:104764930 C>G), RS1000031179 (6:104809420 A>C), RS1000038263 (6:104763823 G>A), RS1000070877 (6:104763603 A>G), RS1000099802 (6:104855635 C>T), RS1000120112 (6:104853713 C>G,T), RS1000120767 (6:104738611 T>A,C), RS1000153745 (6:104731095 G>A), RS1000182988 (6:104810338 G>A), RS1000237536 (6:104778740 C>T), RS1000257220 (6:104816341 T>A,C), RS1000266465 (6:104758939 T>C), RS1000296960 (6:104769863 G>A,T), RS1000360583 (6:104828460 A>G)

Disease associations

OMIM: gene MIM:610876 | disease phenotypes: MIM:616756

GenCC curated gene-disease

Disease	Classification	Inheritance
spastic paraplegia-severe developmental delay-epilepsy syndrome	Definitive	Autosomal recessive

Mondo (2): spastic paraplegia-severe developmental delay-epilepsy syndrome (MONDO:0014764), intellectual disability (MONDO:0001071)

Orphanet (2): Spastic paraplegia-severe developmental delay-epilepsy syndrome (Orphanet:464282), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000520	Proptosis
HP:0000545	Myopia
HP:0000556	Retinal dystrophy
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000822	Hypertension
HP:0001017	Anemic pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001437	Abnormality of the musculature of the lower limbs
HP:0001482	Subcutaneous nodule
HP:0001513	Obesity
HP:0001762	Talipes equinovarus
HP:0001824	Weight loss

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000100_2	Thyroid stimulating hormone levels	7.000000e-06
GCST000175_14	Height	8.000000e-07
GCST000400_1	Menarche (age at onset)	2.000000e-14
GCST001636_2	Obsessive-compulsive disorder	3.000000e-06
GCST001660_5	Neuroblastoma	3.000000e-11
GCST001860_6	Multiple sclerosis	3.000000e-07
GCST002949_4	Epilepsy and lamotrigine-induced maculopapular eruptions	3.000000e-09
GCST003993_1	Menarche (age at onset)	4.000000e-57
GCST003994_8	Age at voice drop	1.000000e-23
GCST004510_3	Sporadic neuroblastoma	1.000000e-13
GCST004562_209	Waist circumference adjusted for body mass index	2.000000e-06
GCST004562_26	Waist circumference adjusted for body mass index	2.000000e-15
GCST004563_172	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	9.000000e-07
GCST004563_246	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	3.000000e-15
GCST004564_194	Waist circumference adjusted for BMI in active individuals	1.000000e-10
GCST004565_4	Waist circumference adjusted for BMI in inactive individuals	4.000000e-07
GCST004946_55	Schizophrenia	8.000000e-09
GCST005580_311	Intraocular pressure	5.000000e-09
GCST006041_7	Major depressive disorder	4.000000e-09
GCST006945_16	Feeling guilty	1.000000e-10
GCST008114_11	Type 2 diabetes	4.000000e-06
GCST009098_3	Resistant hypertension	1.000000e-07
GCST010988_373	Adult body size	3.000000e-09
GCST012227_25	Hip circumference adjusted for BMI	2.000000e-10
GCST90000047_126	Age at first sexual intercourse	9.000000e-10

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:1001253	maculopapular eruption
EFO:0007888	age at voice drop
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0004695	intraocular pressure measurement
EFO:0009595	guilt measurement
EFO:1002006	treatment-resistant hypertension
EFO:0008039	BMI-adjusted hip circumference
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
bisphenol A	increases expression, affects cotreatment, increases methylation	2
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Ethyl Methanesulfonate	increases expression	1
Indomethacin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders