HERPUD1

Summary

HERPUD1 (homocysteine inducible ER protein with ubiquitin like domain 1, HGNC:13744) is a protein-coding gene on chromosome 16q13, encoding Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein (Q15011). Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins.

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the ER stress response. This response includes the inhibition of translation to prevent further accumulation of unfolded proteins, the increased expression of proteins involved in polypeptide folding, known as the unfolded protein response (UPR), and the destruction of misfolded proteins by the ER-associated protein degradation (ERAD) system. This gene may play a role in both UPR and ERAD. Its expression is induced by UPR and it has an ER stress response element in its promoter region while the encoded protein has an N-terminal ubiquitin-like domain which may interact with the ERAD system. This protein has been shown to interact with presenilin proteins and to increase the level of amyloid-beta protein following its overexpression. Alternative splicing of this gene produces multiple transcript variants encoding different isoforms. The full-length nature of all transcript variants has not been determined.

Source: NCBI Gene 9709 — RefSeq curated summary.

At a glance

• GWAS associations: 55
• Clinical variants (ClinVar): 67 total — 1 pathogenic
• MANE Select transcript: NM_014685

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13744
Approved symbol	HERPUD1
Name	homocysteine inducible ER protein with ubiquitin like domain 1
Location	16q13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0025, Mif1, HERP, SUP
Ensembl gene	ENSG00000051108
Ensembl biotype	protein_coding
OMIM	608070
Entrez	9709

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000300302, ENST00000344114, ENST00000379792, ENST00000439977, ENST00000562914, ENST00000563343, ENST00000563781, ENST00000563911, ENST00000564678, ENST00000565966, ENST00000566550, ENST00000567944, ENST00000568358, ENST00000568651, ENST00000568676, ENST00000568814, ENST00000569429, ENST00000569569, ENST00000570273, ENST00000855546, ENST00000855547, ENST00000855548, ENST00000938506, ENST00000951120, ENST00000951121

RefSeq mRNA: 3 — MANE Select: NM_014685 NM_001010989, NM_001272103, NM_014685

CCDS: CCDS10771, CCDS45492

Canonical transcript exons

ENST00000439977 — 8 exons

Exon	Start	End
ENSE00002622166	56932142	56932391
ENSE00003483560	56939895	56940245
ENSE00003494366	56935401	56935475
ENSE00003525382	56935235	56935312
ENSE00003613618	56942132	56942237
ENSE00003614305	56939237	56939359
ENSE00003684299	56936687	56936817
ENSE00003750843	56943126	56944864

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 130.9335 / max 2008.9964, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154292	129.7012	1827
154294	0.9101	367
207891	0.3080	140
154293	0.0142	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.44	gold quality
palpebral conjunctiva	UBERON:0001812	99.37	gold quality
epithelium of nasopharynx	UBERON:0001951	99.31	gold quality
nasopharynx	UBERON:0001728	99.29	gold quality
tonsil	UBERON:0002372	99.19	gold quality
pancreas	UBERON:0001264	99.16	gold quality
tibia	UBERON:0000979	99.11	gold quality
trachea	UBERON:0003126	99.11	gold quality
parietal pleura	UBERON:0002400	99.09	gold quality
rectum	UBERON:0001052	99.07	gold quality
olfactory bulb	UBERON:0002264	99.07	gold quality
seminal vesicle	UBERON:0000998	99.05	gold quality
pylorus	UBERON:0001166	99.05	gold quality
colonic epithelium	UBERON:0000397	99.04	gold quality
pleura	UBERON:0000977	99.04	gold quality
vermiform appendix	UBERON:0001154	99.02	gold quality
right ovary	UBERON:0002118	99.02	gold quality
right lung	UBERON:0002167	99.00	gold quality
visceral pleura	UBERON:0002401	98.98	gold quality
bone marrow cell	CL:0002092	98.96	gold quality
cardia of stomach	UBERON:0001162	98.95	gold quality
parotid gland	UBERON:0001831	98.92	gold quality
left ovary	UBERON:0002119	98.91	gold quality
prostate gland	UBERON:0002367	98.91	gold quality
left lobe of thyroid gland	UBERON:0001120	98.90	gold quality
islet of Langerhans	UBERON:0000006	98.89	gold quality
germinal epithelium of ovary	UBERON:0001304	98.89	gold quality
lymph node	UBERON:0000029	98.87	gold quality
caecum	UBERON:0001153	98.85	gold quality
mammary duct	UBERON:0001765	98.84	gold quality

Single-cell (SCXA)

Detected in 40 experiment(s), a significant marker in 36.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	4252.61
E-CURD-126	yes	3442.58
E-CURD-46	yes	2461.86
E-MTAB-9154	yes	2239.48
E-MTAB-8142	yes	2232.91
E-MTAB-8322	yes	2148.51
E-HCAD-15	yes	1998.74
E-MTAB-10885	yes	1954.83
E-MTAB-10553	yes	1627.87
E-MTAB-10432	yes	1339.99
E-MTAB-6505	yes	1317.59
E-MTAB-9221	yes	989.28
E-MTAB-7407	yes	920.21
E-CURD-88	yes	117.69
E-HCAD-4	yes	70.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, CREB3, CREBRF, CTNNB1, E2F1, MYC

miRNA regulators (miRDB)

68 targeting HERPUD1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3140-3P	99.88	68.47	2069

Literature-anchored findings (GeneRIF, showing 32)

• enhances presnilin-mediated generation of amyloid beta protein (PMID:11799129)
• upregulation by Wnt-1 (PMID:12153396)
• may associate through its ubiquitin-like domain with the 26S proteasome, in this way connecting the protein degradation machinery to the ER membrane and resulting in an efficient ERAD (PMID:12370023)
• The ubiquitin-like domain of Herp most likely plays a role in the regulation of the intracellular level of Herp under ER stress (PMID:14550564)
• Results report the identification of Herp, a gene involved in ER stress-associated protein degradation (ERAD), as a direct target of Luman. (PMID:16940180)
• Expression of Herp protein is up-regulated in response to ER stress, including homocysteine. (PMID:17020760)
• We identified the transcription factor binding site AARE (amino acid response element) by mutational analysis involved in Herp induction in SH-SY5Y cells, and the more significant role of the CREB binding site compared to AARE in HEK 293T cells. (PMID:17020760)
• Herp is in a complex with ubiquitinated proteins and with the 26S proteasome, suggesting that it plays a role in linking substrates with the proteasome. (PMID:18042451)
• Our data suggest that Herp binding to ubiquilin proteins plays an important role in the ERAD pathway and that ubiquilins are specifically involved in degradation of only a subset of ubiquitinated targets, including Herp-dependent ERAD substrates. (PMID:18307982)
• Type II alcoholic patients had a statistically significant higher expression of Herp mRNA due to upregulation of the expression of this neuroprotective cell non-chaperone by toxic effects of ethanol. (PMID:19251110)
• the underlying molecular mechanism(s) whereby Herp counteracts Ca(2+) disturbances will provide insights into the molecular cascade of cell death in dopaminergic neurons (PMID:19447887)
• Herp may play a role in the initiation of the well-known inflammation-like changes in Parkinson disease substantia nigra and serve as a molecular link between degeneration and neuroinflammation in Parkinson disease (PMID:19788048)
• Data show that that 4-trifluoromethyl-celecoxib can inhibit secretion but not transcription of IL-12 (p35/p40) and IL-23 (p40/p19 heterodimers), and that this is associated with HERP function in the endoplasmic reticulum. (PMID:20054003)
• Herp mimics structural determinants of DNA immunologically and can be immunogenic in vivo. Thus, Herp represents a candidate autoantigen for anti-DNA antibodies. (PMID:20147634)
• The results suggest that ERAD molecule Herp may delay the degradation of cytosolic proteins at the ubiquitination step. (PMID:20604806)
• binding of Herp to Hrd1-containing ERAD complexes positively regulates the ubiquitylation activity of these complexes, thus permitting survival of the cell during ER stress. (PMID:21149444)
• Together with histological grade, increased co-expression of MIF and MMP9 in tumor might be a valuable predictor for recurrence, especially for benign meningiomas (PMID:23372434)
• Herp operates as a relevant factor in the defense against glucose starvation by modulating autophagy levels. (PMID:24120520)
• The results indicate that Nrf1 is a transcriptional activator of Herpud1 expression during ER stress, and they suggest Nrf1 is a key player in the regulation of the ER stress response in cells. (PMID:25637874)
• concluded that the HERPUD1-mediated cytoprotective effect against oxidative stress depends on the ITPR and Ca(2+) transfer from the endoplasmic reticulum to mitochondria (PMID:26616647)
• HERPUD1 SNPs are highly associated with polypoidal choroidal vasculopathy. (PMID:26823705)
• Thus, our findings indicated that NQO1 could stabilize Herp protein expression via indirect regulation of synoviolin. (PMID:27084451)
• The authors found that the CREB3/Herp pathway limited the increase in cytosolic Ca2+ concentration and apoptosis early in poliovirus infection and this may reduce the extent of poliovirus-induced damage to the central nervous system during poliomyelitis. (PMID:27405867)
• results indicated that low expression of miR-9-3p results in a high level of Herpud1, which may protect against apoptosis in glioma (PMID:28430789)
• HERP plays an important role in the regulation of host innate immunity in response to ER stress during the infection of RNA viruses. (PMID:28954889)
• The cytosolic relocalization of endoplasmic reticulum chaperone BiP did not require the function of translocon and was counteracted by HERP, a component of endoplasmic reticulum-associated protein degradation. (PMID:29295953)
• This study showed that Herp stability was regulated by synoviolin through lysine ubiquitination-independent proteasomal degradation. (PMID:29863080)
• Herpud1 deficiency could reduce amyloid-beta40 expression and thereby suppress homocysteine-induced atherosclerosis by blocking the JNK/AP1 pathway. (PMID:32488540)
• The Brucella effector BspL targets the ER-associated degradation (ERAD) pathway and delays bacterial egress from infected cells. (PMID:34353909)
• Association of HERPUD1 genetic variant rs2217332 with age-related macular degeneration and polypoidal choroidal vasculopathy in an Indian cohort. (PMID:36220983)
• HERPUD1 promotes ovarian cancer cell survival by sustaining autophagy and inhibit apoptosis via PI3K/AKT/mTOR and p38 MAPK signaling pathways. (PMID:36544104)
• Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification. (PMID:36746840)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	herpud1	ENSDARG00000024314
mus_musculus	Herpud1	ENSMUSG00000031770
rattus_norvegicus	Herpud1	ENSRNOG00000018796
drosophila_melanogaster	Herp	FBGN0031950
caenorhabditis_elegans	tag-353	WBGENE00009112

Paralogs (1): HERPUD2 (ENSG00000122557)

Protein

Protein identifiers

Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein — Q15011 (reviewed: Q15011)

Alternative names: Methyl methanesulfonate (MMF)-inducible fragment protein 1

All UniProt accessions (7): Q15011, H3BP08, H3BQM2, H3BRS4, H3BTA8, H3BTT7, H3BV54

UniProt curated annotations — full annotation on UniProt →

Function. Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. Could enhance presenilin-mediated amyloid-beta protein 40 generation. Binds to ubiquilins and this interaction is required for efficient degradation of CD3D via the ERAD pathway.

Subunit / interactions. Interacts with PSEN1 and PSEN2. Interacts with UBXN6. Interacts with UBQLN1, UBQLN2 and UBQLN4. Component of the HRD1 complex, which comprises at least SYNV1/HRD1, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1. FAM8A1 binding to SYNV1 may promote recruitment of HERPUD1 to the HRD1 complex.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed; in the brain, expression seems to be restricted to neurons and vascular smooth muscle cells. Present in activated microglia in senile plaques in the brain of patients with Alzheimer disease.

Induction. Up-regulated by endoplasmic reticulum stress and CREB3.

Miscellaneous. Although the precise topology is not known, experimental data suggest that both the N- and C-termini face the cytosol.

Isoforms (4)

UniProt ID	Names	Canonical?
Q15011-1	1	yes
Q15011-2	2
Q15011-3	3
Q15011-4	4

RefSeq proteins (3): NP_001010989, NP_001259032, NP_055500* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR039751	HERPUD1/2	Family

Pfam: PF00240

UniProt features (29 total): strand 7, region of interest 4, topological domain 3, splice variant 3, compositionally biased region 2, modified residue 2, transmembrane region 2, helix 2, chain 1, sequence variant 1, turn 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1WGD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15011-F1	63.20	0.11

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 1, 135

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress

MSigDB gene sets: 403 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, CAFFAREL_RESPONSE_TO_THC_UP, GENTILE_RESPONSE_CLUSTER_D3, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (16): ubiquitin-dependent protein catabolic process (GO:0006511), response to unfolded protein (GO:0006986), endoplasmic reticulum unfolded protein response (GO:0030968), retrograde protein transport, ER to cytosol (GO:0030970), regulation of protein ubiquitination (GO:0031396), endoplasmic reticulum calcium ion homeostasis (GO:0032469), response to endoplasmic reticulum stress (GO:0034976), ERAD pathway (GO:0036503), protein targeting to ER (GO:0045047), negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236), regulation of ERAD pathway (GO:1904292), positive regulation of ERAD pathway (GO:1904294), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), intracellular calcium ion homeostasis (GO:0006874), regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902235)

GO Molecular Function (3): transmembrane transporter binding (GO:0044325), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (6): Hrd1p ubiquitin ligase complex (GO:0000836), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum quality control compartment (GO:0044322), Lewy body core (GO:1990037)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PERK regulates gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ERAD pathway	3
cellular anatomical structure	3
protein ubiquitination	2
response to endoplasmic reticulum stress	2
endoplasmic reticulum	2
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	2
regulation of response to endoplasmic reticulum stress	2
regulation of intrinsic apoptotic signaling pathway	2
modification-dependent protein catabolic process	1
response to topologically incorrect protein	1
cellular response to unfolded protein	1
intracellular signal transduction	1
protein exit from endoplasmic reticulum	1
endoplasmic reticulum to cytosol transport	1
regulation of protein modification by small protein conjugation or removal	1
intracellular calcium ion homeostasis	1
cellular response to stress	1
proteasomal protein catabolic process	1
response to chemical	1
protein targeting	1
establishment of protein localization to endoplasmic reticulum	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
negative regulation of response to endoplasmic reticulum stress	1
negative regulation of intrinsic apoptotic signaling pathway	1
regulation of proteasomal protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
regulation of ERAD pathway	1
positive regulation of response to endoplasmic reticulum stress	1
ubiquitin-dependent protein catabolic process	1
positive regulation of protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
intrinsic apoptotic signaling pathway	1
negative regulation of intracellular signal transduction	1
negative regulation of apoptotic signaling pathway	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
protein binding	1
enzyme-substrate adaptor activity	1
binding	1
ER ubiquitin ligase complex	1

Protein interactions and networks

STRING

860 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HERPUD1	PDIA3	P30101	796
HERPUD1	PRKCSH	P14314	769
HERPUD1	XBP1	P17861	767
HERPUD1	HSPA5	P11021	755
HERPUD1	EDEM1	Q92611	700
HERPUD1	DNAJB9	Q9UBS3	697
HERPUD1	RAD23A	P54725	637
HERPUD1	DNAJC3	Q13217	628
HERPUD1	ATF6	P18850	625
HERPUD1	SEL1L	Q9UBV2	603
HERPUD1	MANF	P55145	596
HERPUD1	PKD2L1	Q9P0L9	584
HERPUD1	PDIA4	P13667	584
HERPUD1	ERO1B	Q86YB8	561
HERPUD1	SYVN1	Q86TM6	558

IntAct

42 interactions, top by confidence:

A	B	Type	Score
SEL1L	OS9	psi-mi:“MI:0914”(association)	0.860
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SYVN1	OS9	psi-mi:“MI:0914”(association)	0.690
	HERPUD1	psi-mi:“MI:0915”(physical association)	0.610
	HERPUD1	psi-mi:“MI:0195”(covalent binding)	0.610
SYVN1	HERPUD1	psi-mi:“MI:0914”(association)	0.460
AMFR	HERPUD1	psi-mi:“MI:0407”(direct interaction)	0.440
UBXN6	HERPUD1	psi-mi:“MI:0915”(physical association)	0.400
HERPUD1	CAPN15	psi-mi:“MI:0915”(physical association)	0.400
HERPUD1	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
HERPUD1	CCR2	psi-mi:“MI:0915”(physical association)	0.370
HERPUD1	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
HERPUD1	CHRM2	psi-mi:“MI:0915”(physical association)	0.370
ARHGDIA	HERPUD1	psi-mi:“MI:0915”(physical association)	0.370
HERPUD1	XRCC6	psi-mi:“MI:0915”(physical association)	0.370
EWSR1	HERPUD1	psi-mi:“MI:0915”(physical association)	0.370
FAM8A1	HERPUD1	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350

BioGRID (230): HERPUD1 (Biochemical Activity), HERPUD1 (Biochemical Activity), HERPUD1 (Reconstituted Complex), HERPUD1 (Biochemical Activity), CAPN15 (Affinity Capture-MS), HERPUD1 (Two-hybrid), HERPUD1 (Affinity Capture-Western), HERPUD1 (Affinity Capture-Western), HERPUD1 (Co-fractionation), HERPUD1 (Two-hybrid), HERPUD1 (Affinity Capture-Western), SH3RF1 (Affinity Capture-Western), SH3RF1 (Reconstituted Complex), HERPUD1 (Biochemical Activity), CAPN15 (Affinity Capture-MS)

ESM2 similar proteins: A0A482PJY4, A2AH22, A3KPW9, A4IH17, A5D9M6, A7X5R6, A8Y4B2, D5LXJ0, E7FAG6, O22197, O42967, O74757, P0CH30, P38428, P46379, Q09463, Q0II22, Q15011, Q20798, Q2KIS3, Q3KPV4, Q5R5B0, Q68FU0, Q6DIP3, Q6IRP0, Q6MG49, Q6P135, Q6PA26, Q7T0Q3, Q7ZXQ3, Q8C5U9, Q8LPN7, Q8WUU8, Q91W67, Q91YL2, Q94AK4, Q96S82, Q9BV68, Q9C0C7, Q9C1X4

Diamond homologs: Q0P5H8, Q15011, Q28DF1, Q5R5B0, Q66HH4, Q6NYI0, Q7ZXQ3, Q9BSE4, Q9JJC9, Q9JJK5

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CREB3	“up-regulates quantity by expression”	HERPUD1	“transcriptional regulation”
HERPUD1	“up-regulates quantity by stabilization”	HSPA5	relocalization
SYVN1	“up-regulates activity”	HERPUD1	binding
CREBRF	“up-regulates quantity by expression”	HERPUD1	“transcriptional regulation”
SH3RF1	“up-regulates activity”	HERPUD1	ubiquitination
Unfolded_Proteins	“up-regulates quantity by expression”	HERPUD1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 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.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	38.8×	2e-06
ubiquitin-dependent protein catabolic process	6	15.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	48
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
981834	NM_014685.4(HERPUD1):c.584_585del (p.Phe195fs)	Pathogenic

SpliceAI

1421 predictions. Top by Δscore:

Variant	Effect	Δscore
16:56932320:C:G	donor_gain	1.0000
16:56935227:A:AG	acceptor_gain	1.0000
16:56935227:AT:A	acceptor_gain	1.0000
16:56935228:T:A	acceptor_gain	1.0000
16:56935228:T:G	acceptor_gain	1.0000
16:56935233:A:AG	acceptor_gain	1.0000
16:56935234:G:GG	acceptor_gain	1.0000
16:56935234:GC:G	acceptor_gain	1.0000
16:56935308:CAAAG:C	donor_loss	1.0000
16:56935309:AAAG:A	donor_loss	1.0000
16:56935310:AAGGT:A	donor_loss	1.0000
16:56935311:AGGT:A	donor_loss	1.0000
16:56935312:GGTAC:G	donor_loss	1.0000
16:56935313:G:GA	donor_loss	1.0000
16:56935314:T:A	donor_loss	1.0000
16:56936677:A:AG	acceptor_gain	1.0000
16:56936683:TTAGG:T	acceptor_loss	1.0000
16:56936684:TAGGT:T	acceptor_loss	1.0000
16:56936685:AGGT:A	acceptor_gain	1.0000
16:56936686:G:GA	acceptor_loss	1.0000
16:56936686:GGT:G	acceptor_gain	1.0000
16:56936686:GGTG:G	acceptor_gain	1.0000
16:56936771:G:T	donor_gain	1.0000
16:56936815:AAGGT:A	donor_loss	1.0000
16:56936816:AGGTG:A	donor_loss	1.0000
16:56936817:GGT:G	donor_loss	1.0000
16:56936818:G:GG	donor_gain	1.0000
16:56936818:GTG:G	donor_loss	1.0000
16:56936819:T:A	donor_loss	1.0000
16:56939360:G:GG	donor_gain	1.0000

AlphaMissense

2572 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:56935254:T:C	L56S	1.000
16:56932358:G:C	K38N	0.999
16:56932358:G:T	K38N	0.999
16:56935266:G:T	G60V	0.999
16:56935422:C:G	H83D	0.999
16:56935426:T:C	L84P	0.999
16:56940155:C:A	A272D	0.999
16:56940167:T:A	V276D	0.999
16:56940175:A:C	S279R	0.999
16:56940177:T:A	S279R	0.999
16:56940177:T:G	S279R	0.999
16:56932354:T:C	L37P	0.998
16:56932366:T:C	L41P	0.998
16:56935249:G:C	Q54H	0.998
16:56935249:G:T	Q54H	0.998
16:56935266:G:A	G60E	0.998
16:56935275:T:C	L63S	0.998
16:56940134:T:C	L265S	0.998
16:56940154:G:C	A272P	0.998
16:56940184:T:G	Y282D	0.998
16:56932289:G:C	K15N	0.997
16:56932289:G:T	K15N	0.997
16:56935248:A:C	Q54P	0.997
16:56935257:T:A	I57N	0.997
16:56935257:T:C	I57T	0.997
16:56935424:T:A	H83Q	0.997
16:56935424:T:G	H83Q	0.997
16:56940130:T:A	W264R	0.997
16:56940130:T:C	W264R	0.997
16:56940223:G:A	G295R	0.997

dbSNP variants (sampled 300 via entrez): RS1000020476 (16:56930255 T>G), RS1000239191 (16:56930449 C>T), RS1000552613 (16:56936501 G>A,T), RS1000791053 (16:56941550 A>G), RS1001276154 (16:56934580 G>T), RS1001816810 (16:56938223 G>A,T), RS1002045531 (16:56944020 G>C), RS1002101260 (16:56931596 G>A), RS1002661571 (16:56934449 C>T), RS1003458634 (16:56939121 G>A,T), RS1004154069 (16:56942401 G>A,C,T), RS1005833185 (16:56931084 G>A), RS1005862882 (16:56930847 A>C,G), RS1006135113 (16:56937327 A>G), RS1006487451 (16:56933250 G>A)

Disease associations

OMIM: gene MIM:608070 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

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

GWAS associations

55 associations (top):

Study	Trait	p-value
GCST000331_1	HDL cholesterol	4.000000e-93
GCST000753_11	Metabolic syndrome	3.000000e-06
GCST001904_2	HDL cholesterol	1.000000e-24
GCST002094_5	Crohn’s disease	1.000000e-08
GCST002469_2	HDL cholesterol	2.000000e-16
GCST002744_1	HDL Cholesterol in HIV-infection	4.000000e-07
GCST002875_127	Diisocyanate-induced asthma	1.000000e-06
GCST003363_2	HDL cholesterol levels	1.000000e-16
GCST004704_1	Cardiovascular risk factors	1.000000e-23
GCST005194_146	Coronary artery disease	3.000000e-08
GCST006003_23	Triglyceride levels	1.000000e-12
GCST006005_47	High density lipoprotein cholesterol levels	2.000000e-300
GCST006034_1	Total cholesterol levels	2.000000e-32
GCST008070_119	HDL cholesterol levels	7.000000e-20
GCST008070_139	HDL cholesterol levels	4.000000e-12
GCST008070_45	HDL cholesterol levels	2.000000e-118
GCST008070_67	HDL cholesterol levels	5.000000e-126
GCST008074_131	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-09
GCST008074_157	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-10
GCST008075_1	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	8.000000e-216
GCST008075_128	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-23
GCST008075_136	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-299
GCST008075_210	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-20
GCST008077_23	LDL cholesterol levels	5.000000e-07
GCST008077_87	LDL cholesterol levels	4.000000e-06
GCST008078_127	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-08
GCST008078_26	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-10
GCST008079_13	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-18
GCST008079_153	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-15
GCST008083_121	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-10

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0000195	metabolic syndrome
EFO:0006995	response to diisocyanate
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0010377	phosphatidylcholine 34:3 measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects expression, affects cotreatment, increases expression	9
Tunicamycin	increases expression	7
sodium arsenite	increases abundance, increases expression	6
Benzo(a)pyrene	decreases expression, increases methylation	6
Valproic Acid	affects expression, affects cotreatment, increases expression	6
bisphenol A	affects expression, decreases methylation, increases expression	3
cadmium sulfate	decreases expression, increases expression	3
Cannabidiol	increases expression, affects cotreatment	3
Dronabinol	affects expression, affects cotreatment, increases expression, decreases expression	3
Aflatoxin B1	decreases expression, decreases methylation	3
Thapsigargin	increases expression	3
beta-N-methylamino-L-alanine	increases expression	2
didecyldimethylammonium	increases expression	2
perfluorooctane sulfonic acid	increases expression	2
Acetylcysteine	increases expression, decreases reaction	2
Amiodarone	increases expression	2
Carbamazepine	affects expression	2
Copper	affects binding, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silver	increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, affects expression, increases reaction	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
methylmercuric chloride	increases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	increases expression	1
potassium perchlorate	increases expression	1
beta-lapachone	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome