ERN2

Summary

ERN2 (endoplasmic reticulum to nucleus signaling 2, HGNC:16942) is a protein-coding gene on chromosome 16p12.2, encoding Serine/threonine-protein kinase/endoribonuclease IRE2 (Q76MJ5). Induces translational repression through 28S ribosomal RNA cleavage in response to ER stress.

Enables several functions, including ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including apoptotic chromosome condensation; negative regulation of DNA-templated transcription; and rRNA catabolic process. Located in endoplasmic reticulum.

Source: NCBI Gene 10595 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Clinical variants (ClinVar): 74 total
• GTEx eGene: eQTL in 5 tissues, sQTL in 2 (q < 0.05)
• ChEMBL bioactivity: 4 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.21 (unconstrained)
• MANE Select transcript: NM_033266
• Notable: 74 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16942
Approved symbol	ERN2
Name	endoplasmic reticulum to nucleus signaling 2
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	IRE1b
Ensembl gene	ENSG00000134398
Ensembl biotype	protein_coding
OMIM	604034
Entrez	10595

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 6 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000256797

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 3: 1, TSL 5: 3

ENST00000256797, ENST00000457008, ENST00000561478, ENST00000562458, ENST00000562562, ENST00000566565, ENST00000569903, ENST00000885424, ENST00000885425, ENST00000885426, ENST00000885427, ENST00000885428, ENST00000885429, ENST00000885430, ENST00000885431, ENST00000885432, ENST00000885433, ENST00000977706, ENST00000977707, ENST00000977708, ENST00001138809

RefSeq mRNA: 2 — MANE Select: NM_033266 NM_001308220, NM_033266

CCDS: CCDS32407, CCDS76845

Canonical transcript exons

ENST00000256797 — 22 exons

Exon	Start	End
ENSE00001107253	23690310	23691043
ENSE00001107271	23700539	23700704
ENSE00001107291	23700959	23701114
ENSE00001107306	23692184	23692331
ENSE00001107309	23694728	23694927
ENSE00001107314	23695019	23695118
ENSE00001316879	23710172	23710244
ENSE00002610850	23713095	23713222
ENSE00003472520	23695200	23695389
ENSE00003562165	23702152	23702273
ENSE00003588358	23706754	23706861
ENSE00003615710	23695894	23695978
ENSE00003622668	23702390	23702537
ENSE00003627299	23710516	23710549
ENSE00003654782	23710913	23711018
ENSE00003677599	23702624	23702702
ENSE00003683610	23706330	23706431
ENSE00003684731	23704883	23705147
ENSE00003688466	23707007	23707079
ENSE00003756163	23691129	23691196
ENSE00003758369	23691963	23692090
ENSE00003760193	23691302	23691425

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 98.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5655 / max 98.7458, expressed in 57 samples.

Highest expression (Bgee): nasal cavity epithelium, pancreatic ductal cell, mucosa of transverse colon, mucosa of paranasal sinus, olfactory bulb.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ERN2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 5 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

7 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Prostate	eqtl	1.7e-03	-1.03	16:24651291:C:A
Colon Transverse	eqtl	2.0e-03	-0.09	16:23697013:C:CA
Stomach	sqtl	1.9e-02	-0.36	16:23700862:A:G
Lung	sqtl	2.6e-02	-0.31	16:23771747:C:T
Pancreas	eqtl	3.0e-02	-0.83	16:23229113:C:T
Testis	eqtl	3.6e-02	-1.30	16:22717374:G:A
Minor Salivary Gland	eqtl	4.6e-02	+0.44	16:23276976:G:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
156781	0.5655	57

Top tissues by expression

showing 100 of 262 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	98.45	gold quality
pancreatic ductal cell	CL:0002079	97.20	gold quality
mucosa of transverse colon	UBERON:0004991	97.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.88	gold quality
olfactory bulb	UBERON:0002264	96.00	silver quality
epithelium of bronchus	UBERON:0002031	95.89	gold quality
bronchus	UBERON:0002185	95.72	gold quality
bronchial epithelial cell	CL:0002328	95.67	gold quality
colonic mucosa	UBERON:0000317	95.26	gold quality
rectum	UBERON:0001052	95.24	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.89	gold quality
type B pancreatic cell	CL:0000169	94.72	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	94.53	gold quality
triceps brachii	UBERON:0001509	94.39	silver quality
gluteal muscle	UBERON:0002000	93.87	silver quality
diaphragm	UBERON:0001103	93.63	silver quality
gall bladder	UBERON:0002110	93.53	gold quality
pylorus	UBERON:0001166	93.42	gold quality
buccal mucosa cell	CL:0002336	93.05	gold quality
cardia of stomach	UBERON:0001162	91.46	gold quality
trachea	UBERON:0003126	91.20	gold quality
cervix squamous epithelium	UBERON:0006922	90.99	silver quality
epithelial cell of pancreas	CL:0000083	89.75	silver quality
nasal cavity mucosa	UBERON:0001826	89.73	gold quality
vena cava	UBERON:0004087	89.42	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	89.08	silver quality
epithelium of nasopharynx	UBERON:0001951	88.42	gold quality
vastus lateralis	UBERON:0001379	88.29	silver quality
transverse colon	UBERON:0001157	87.96	gold quality
lateral globus pallidus	UBERON:0002476	87.68	gold quality
thymus	UBERON:0002370	87.43	silver quality
tongue squamous epithelium	UBERON:0006919	87.34	silver quality
quadriceps femoris	UBERON:0001377	86.88	silver quality
myocardium	UBERON:0002349	86.82	silver quality
superior surface of tongue	UBERON:0007371	86.45	gold quality
inferior olivary complex	UBERON:0002127	86.20	silver quality
cerebellar vermis	UBERON:0004720	85.94	silver quality
ventral tegmental area	UBERON:0002691	85.75	silver quality
left ventricle myocardium	UBERON:0006566	85.74	silver quality
endothelial cell	CL:0000115	85.68	silver quality
dorsal plus ventral thalamus	UBERON:0001897	85.68	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.56	silver quality
cervix epithelium	UBERON:0004801	85.56	silver quality
subthalamic nucleus	UBERON:0001906	85.54	silver quality
ileal mucosa	UBERON:0000331	85.40	gold quality
tongue	UBERON:0001723	85.40	gold quality
inferior vagus X ganglion	UBERON:0005363	85.35	silver quality
jejunum	UBERON:0002115	85.10	gold quality
duodenum	UBERON:0002114	85.09	gold quality
parotid gland	UBERON:0001831	85.07	silver quality
renal medulla	UBERON:0000362	84.99	silver quality
medulla oblongata	UBERON:0001896	84.78	silver quality
nipple	UBERON:0002030	84.43	silver quality
small intestine Peyer’s patch	UBERON:0003454	84.40	gold quality
body of tongue	UBERON:0011876	84.40	silver quality
heart right ventricle	UBERON:0002080	84.35	silver quality
cardiac muscle of right atrium	UBERON:0003379	84.34	silver quality
orbitofrontal cortex	UBERON:0004167	84.33	silver quality
palpebral conjunctiva	UBERON:0001812	84.30	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.26	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	84.13	silver quality
minor salivary gland	UBERON:0001830	84.08	gold quality
pericardium	UBERON:0002407	84.00	silver quality
jejunal mucosa	UBERON:0000399	83.98	gold quality
mucosa of urinary bladder	UBERON:0001259	83.89	silver quality
body of stomach	UBERON:0001161	83.67	gold quality
periodontal ligament	UBERON:0008266	83.50	silver quality
substantia nigra pars compacta	UBERON:0001965	83.47	silver quality
biceps brachii	UBERON:0001507	83.45	silver quality
trigeminal ganglion	UBERON:0001675	83.44	silver quality
pharyngeal mucosa	UBERON:0000355	83.43	gold quality
hair follicle	UBERON:0002073	83.42	silver quality
superficial temporal artery	UBERON:0001614	83.41	silver quality
pons	UBERON:0000988	83.17	silver quality
mouth mucosa	UBERON:0003729	83.15	gold quality
superior vestibular nucleus	UBERON:0007227	83.14	silver quality
stomach	UBERON:0000945	83.12	gold quality
small intestine	UBERON:0002108	82.99	gold quality
saliva-secreting gland	UBERON:0001044	82.96	gold quality
male germ cell	CL:0000015	82.87	silver quality
mucosa of stomach	UBERON:0001199	82.79	gold quality
upper arm skin	UBERON:0004263	82.48	silver quality
saphenous vein	UBERON:0007318	82.33	silver quality
dorsal root ganglion	UBERON:0000044	82.16	silver quality
urethra	UBERON:0000057	81.86	gold quality
sperm	CL:0000019	81.56	silver quality
layer of synovial tissue	UBERON:0007616	80.05	silver quality
globus pallidus	UBERON:0001875	79.98	silver quality
synovial joint	UBERON:0002217	79.97	silver quality
penis	UBERON:0000989	79.41	silver quality
caecum	UBERON:0001153	79.11	gold quality
tendon of biceps brachii	UBERON:0008188	79.07	silver quality
fundus of stomach	UBERON:0001160	79.00	gold quality
trabecular bone tissue	UBERON:0002483	78.81	silver quality
entorhinal cortex	UBERON:0002728	78.68	silver quality
parietal lobe	UBERON:0001872	78.37	silver quality
medial globus pallidus	UBERON:0002477	78.21	silver quality
intestine	UBERON:0000160	78.12	gold quality
oviduct epithelium	UBERON:0004804	77.96	silver quality
mammalian vulva	UBERON:0000997	77.93	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	49.51
E-ANND-3	yes	6.86

HPA expression

RNA tissue specificity: Group enriched

44 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Stomach 1	tissue	49.0	high
Colon	tissue	27.1	high
Rectum	tissue	21.6	high
Cervix	tissue	18.3	not detected
Gallbladder	tissue	15.9	medium
Duodenum	tissue	12.1	high
Small intestine	tissue	8.7	high
Appendix	tissue	2.8	high
Salivary gland	tissue	2.7	medium
Urinary bladder	tissue	1.6
Choroid plexus	tissue	1.4
Nucleus accumbens	tissue	1.2
Hippocampus	tissue	1.1	low
Locus coeruleus	tissue	1.0
Postcentral gyrus	tissue	0.9
Smooth muscle	tissue	0.8	not detected
Prostate	tissue	0.7	not detected
Lung	tissue	0.4	low
Vagina	tissue	0.3	not detected
Esophagus	tissue	0.3	not detected
Fallopian tube	tissue	0.3	not detected
Pituitary gland	tissue	0.2
Seminal vesicle	tissue	0.1	low
Adipose tissue	tissue	0.1	not detected
Pancreas	tissue	0.1	low
Spinal cord	tissue	0.1
Adrenal gland	tissue	0.1	low
Ventral forebrain	tissue	0.1
Olfactory bulb	tissue	0.1
Lymph node	tissue	0.0	low
Breast	tissue	0.0	low
Testis	tissue	0.0	high
Heart muscle	tissue	0.0	low
Cerebral cortex	tissue	0.0	low
Parathyroid gland	tissue	0.0	low
Skeletal muscle	tissue	0.0	low
Epididymis	tissue	0.0	low
Basal ganglia	tissue	0.0	low
Placenta	tissue	0.0	low
Cerebellum	tissue	0.0	low
Thyroid gland	tissue	0.0	low
Spleen	tissue	0.0	low
Kidney	tissue	0.0	low
Tonsil	tissue	0.0	medium

Brain sub-regions (HPA Brain Atlas): detected in 185; highest nTPM — Flocculonodular lobe (2.3), Vermis (2.0), Precentral gyrus (1.8), Cerebellar cortex (1.7), Parieto-temporal junction (white matter) (1.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ERN2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

16 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-3674	97.01	68.86	1171
HSA-MIR-212-5P	96.83	67.43	950

Functional genomics

gnomAD constraint: pLI 1e-36, LOEUF 1.21, missense Z 0.00272 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000256797 — one region, missense o/e 1.02.

Literature-anchored findings (GeneRIF, showing 8)

• The structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and unfolded protein response (UPR) signaling. (PMID:16973740)
• RNase domain of IRE1 determines the functional specificities of each of these isoforms. (PMID:18242182)
• Data show that IRE1beta represses translation on the ER membrane but not in the cytosol, and that this selective repression depends on the RNase activity of IRE1beta. (PMID:21146530)
• The luminal event mediated by IRE1beta involves direct interaction with unfolded proteins rather than association/dissociation with BiP. (PMID:23236464)
• ER stress-regulated IRE1 dependent decay is involved in regulation of hepatic diseases. (review) (PMID:27774654)
• A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in idiopathic pulmonary fibrosis (IPF), providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. (PMID:30973754)
• IRE1beta acts as a dominant-negative suppressor of IRE1alpha and affect how barrier epithelial cells manage the response to stress at the host-environment interface. (PMID:31985747)
• EEF1A2 and ERN2 could potentially discriminate metastatic status of mediastinal lymph node in lung adenocarcinomas harboring EGFR 19Del/L858R mutations. (PMID:32881299)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ern1	ENSDARG00000013997
danio_rerio		ENSDARG00000087767
mus_musculus	Ern2	ENSMUSG00000030866
rattus_norvegicus	Ern2	ENSRNOG00000018974
drosophila_melanogaster	Ire1	FBGN0261984
caenorhabditis_elegans		WBGENE00002147

Paralogs (1): ERN1 (ENSG00000178607)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1349436) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased susceptibility to induced colitis	4

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Dictyostelium discoideum	Q557G1	69.6%	Diamond
Trichoderma reesei QM6a	G0RBE3	53.2%	Diamond
Arabidopsis thaliana	Q9C5S2	47.4%	Diamond
Schizosaccharomyces pombe 972h-	O94537	45.0%	Diamond
Oryza sativa Japonica Group	Q7XIT1	42.9%	Diamond
Saccharomyces cerevisiae S288C	P32361	42.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CACNG3	protein-coding	10368
LINC02194	ncRNA	105371142
PLK1	protein-coding	5347
PRKCB	protein-coding	5579
CHP2	protein-coding	63928
MIR1273H	ncRNA	102466247
NDUFAB1	protein-coding	4706
PALB2	protein-coding	79728
DCTN5	protein-coding	84516
UBFD1	protein-coding	56061

Protein

Protein identifiers

Serine/threonine-protein kinase/endoribonuclease IRE2 — Q76MJ5 (reviewed: Q76MJ5)

Alternative names: Endoplasmic reticulum-to-nucleus signaling 2, Inositol-requiring protein 2, Ire1-beta

All UniProt accessions (5): E7ETG2, H3BSU1, H3BTW8, H3BUU2, Q76MJ5

UniProt curated annotations — full annotation on UniProt →

Function. Induces translational repression through 28S ribosomal RNA cleavage in response to ER stress. Pro-apoptotic. Appears to play no role in the unfolded-protein response, unlike closely related proteins.

Subcellular location. Endoplasmic reticulum membrane.

Post-translational modifications. Autophosphorylated.

Activity regulation. The kinase domain is activated by trans-autophosphorylation. Kinase activity is required for activation of the endoribonuclease domain.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.

RefSeq proteins (2): NP_001295149, NP_150296* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR010513	KEN_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR018391	PQQ_b-propeller_rpt	Repeat
IPR038357	KEN_sf	Homologous_superfamily
IPR045133	IRE1/2-like	Family

Pfam: PF00069, PF06479

Catalyzed reactions (Rhea)

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (51 total): sequence conflict 28, sequence variant 10, binding site 2, topological domain 2, domain 2, signal peptide 1, chain 1, mutagenesis site 1, transmembrane region 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
9I3F	Crystal structure of the AGR2 and IRE1beta_loop complex	X-RAY DIFFRACTION	1.9
9I3U	Cryo-EM structure of the AGR2 dimer in complex with the monomeric IRE1beta luminal domain	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q76MJ5-F1	70.91	0.33

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; endoplasmic reticulum

Antibody reliability (HPA): IH approved · IF approved

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)

Position	Role
637	proton acceptor

Ligand- & substrate-binding residues (2)

Position	Role
526–534	ATP
548	ATP

Mutagenesis-validated functional residues (1)

Position	Phenotype
548	loss of autophosphorylation, of induction of apoptosis and of 28s rrna cleavage, attenuation of repression of protein synthesis.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 103 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, GOMF_NUCLEASE_ACTIVITY, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_CHROMOSOME_CONDENSATION, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_JNK_CASCADE, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (14): DNA-templated transcription (GO:0006351), mRNA processing (GO:0006397), protein phosphorylation (GO:0006468), rRNA catabolic process (GO:0016075), apoptotic chromosome condensation (GO:0030263), response to endoplasmic reticulum stress (GO:0034976), IRE1-mediated unfolded protein response (GO:0036498), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of JNK cascade (GO:0046330), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), regulation of DNA-templated transcription (GO:0006355), RNA catabolic process (GO:0006401), apoptotic process (GO:0006915), endoplasmic reticulum unfolded protein response (GO:0030968)

GO Molecular Function (15): magnesium ion binding (GO:0000287), endonuclease activity (GO:0004519), RNA endonuclease activity (GO:0004521), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), hydrolase activity (GO:0016787), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), RNA nuclease activity (GO:0004540), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum quality control compartment (GO:0044322), IRE1-TRAF2-ASK1 complex (GO:1990604), endoplasmic reticulum membrane (GO:0005789)

GO top-level categories

59 GO namespaces:

Category	Terms
DNA-templated transcription	2
response to endoplasmic reticulum stress	2
nuclease activity	2
protein kinase activity	2
catalytic activity	2
gene expression	1
RNA biosynthetic process	1
RNA processing	1
mRNA metabolic process	1
phosphorylation	1
protein modification process	1
RNA catabolic process	1
rRNA metabolic process	1
chromosome condensation	1
apoptotic nuclear changes	1
cellular response to stress	1
endoplasmic reticulum unfolded protein response	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
intrinsic apoptotic signaling pathway	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to unfolded protein	1
intracellular signal transduction	1
metal ion binding	1
endonuclease activity	1
RNA nuclease activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
catalytic activity, acting on RNA	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
cellular anatomical structure	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 34 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
apoptotic chromosome condensation	BP	mutant phenotype
negative regulation of DNA-templated transcription	BP	mutant phenotype
protein phosphorylation	BP	direct assay
rRNA catabolic process	BP	direct assay
endoplasmic reticulum	CC	direct assay
ATP binding	MF	direct assay
endonuclease activity	MF	direct assay
magnesium ion binding	MF	direct assay
protein serine/threonine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 650 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERN2	XBP1	P17861	831
ERN2	ATF6	P18850	795
ERN2	ATF6B	Q99941	683
ERN2	HSPA5	P11021	675
ERN2	MBTPS2	O43462	553
ERN2	MBTPS1	Q14703	511
ERN2	EDEM1	Q92611	509
ERN2	DNAJC3	Q13217	506
ERN2	RTCB	Q9Y3I0	484
ERN2	DDIT3	P35638	468
ERN2	ATF4	P18848	467
ERN2	DNAJB9	Q9UBS3	465
ERN2	CANX	P27824	455
ERN2	DCTN5	Q9BTE1	455
ERN2	AGR2	O95994	445

IntAct

Human interaction partners of ERN2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
SEC16A	association	0.350	1

BioGRID (25 interactions; top human partners by supporting records): CNP (Affinity Capture-MS), CSK (Synthetic Lethality), DNAJB11 (Affinity Capture-MS), DNAJC3 (Affinity Capture-MS), FXR1 (Cross-Linking-MS (XL-MS)), GANAB (Affinity Capture-MS), HSP90B1 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), ISYNA1 (Co-fractionation), KEAP1 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), P4HB (Affinity Capture-MS), PDIA4 (Affinity Capture-MS), PDIA6 (Affinity Capture-MS), PLEKHA4 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for ERN2: 74 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	9
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 2,138):

Position(s)	Effect	Δscore	Sites
16:23691127	donor_loss	1.0000
16:23691198	acceptor_loss	1.0000
16:23692098	acceptor_gain	1.0000
16:23694928–23694929	acceptor_loss	1.0000	5
16:23695199	donor_loss	1.0000
16:23702703–23702704	acceptor_loss	1.0000	6
16:23710911–23710912	donor_loss	1.0000	5
16:23710916	donor_gain	1.0000
16:23711019–23711020	acceptor_loss	1.0000	6
16:23713094	donor_loss	1.0000	2

AlphaMissense

1,433 missense substitutions predicted likely pathogenic (of 5,943 scored), across 405 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D660	8	0.976	0.994
D705	8	0.959	0.981
F661	8	0.958	0.985
D637	8	0.939	0.982
N642	8	0.937	0.981
N855	8	0.936	0.978
H635	8	0.929	0.981
F886	8	0.926	0.992
F707	8	0.923	0.986
H859	8	0.905	0.981
D796	8	0.866	0.921
H571	8	0.860	0.974
D569	8	0.855	0.930
D131	8	0.853	0.951
F882	8	0.844	0.980
H629	8	0.830	0.933
F906	8	0.825	0.928
D848	8	0.807	0.920
F791	8	0.746	0.953
W823	7	0.971	0.992

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Colon Adenocarcinoma, Pancreatic Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	unfavorable	1.09e-08

Disease associations

OMIM: gene MIM:604034 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105932 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 14,842 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

4 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2028663	DABRAFENIB	4	13,060
CHEMBL603469	LESTAURTINIB	3
CHEMBL3039525	GOLVATINIB	2	555
CHEMBL3408248	AZD-8186	1	1,227

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — IRE family

Binding affinities (BindingDB)

13 measured of 13 human assays (14 total across all organisms); most potent 13 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	5.6 nM	US-8822500: Tyrosine kinase inhibitors
Staurosporine, 8	IC50	6.5 nM
2-chloro-N-[5-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]naphthalen-1-yl]benzenesulfonamide	IC50	10 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
N-[(2-chlorophenyl)methyl]-4-methyl-3-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]benzamide	IC50	52 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
2-chloro-N-[6-methyl-5-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxynaphthalen-1-yl]benzenesulfonamide	IC50	98 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
2-chloro-N-[2-fluoro-4-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]phenyl]benzenesulfonamide	IC50	117 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
N-(2-chlorophenyl)-4-methyl-3-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]benzamide	IC50	228 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
2-chloro-N-[4-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxynaphthalen-1-yl]benzenesulfonamide	IC50	296 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
4-[4-[4-(1H-benzimidazol-2-ylmethyl)phenoxy]-1,3-thiazol-5-yl]-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine	IC50	439 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
1-(2-chlorophenyl)-N-[2-fluoro-4-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxyphenyl]methanesulfonamide	IC50	961 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
CHEMBL5653589	KD	1440 nM
2-chloro-N-[2-fluoro-4-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxyphenyl]benzenesulfonamide	IC50	6200 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
4-[3-[4-(1H-benzimidazol-2-ylmethyl)phenoxy]pyrazin-2-yl]-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine	IC50	7300 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors

ChEMBL bioactivities

12 potent at pChembl≥5 of 12 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.76	IC50	17.4	nM	STAUROSPORINE
7.66	IC50	22.1	nM	STAUROSPORINE
7.18	IC50	65.8	nM	STAUROSPORINE
6.94	Kd	116	nM	DABRAFENIB
6.54	Kd	292	nM	LESTAURTINIB
6.04	Kd	908	nM	K-252A
6.01	Kd	986	nM	GOLVATINIB
5.87	Kd	1337	nM	CHEMBL5653589
5.82	Kd	1500	nM	AZD-8186
5.77	ED50	1707	nM	CHEMBL5653589
5.67	Kd	2112	nM	CHEMBL3752910
5.57	ED50	2696	nM	CHEMBL3752910

PubChem BioAssay actives

10 with measured affinity, of 263 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715351: Inhibition of human ERN2 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0174	uM
Dabrafenib	1424998: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1160	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	1424998: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2920	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	1424998: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.9080	uM
1-N’-[2-fluoro-4-[[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]-4-pyridinyl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1424998: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.9860	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148337: Binding affinity to human ERN2 incubated for 45 mins by Kinobead based pull down assay	kd	1.3374	uM
8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide	1424998: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.5000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148337: Binding affinity to human ERN2 incubated for 45 mins by Kinobead based pull down assay	kd	2.1119	uM

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, affects methylation, decreases expression, increases abundance	3
Benzo(a)pyrene	affects methylation, increases methylation	2
aristolochic acid I	increases expression	1
beta-N-methylamino-L-alanine	decreases expression	1
chlortoluron	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
arsenic trichloride	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
Gold	increases expression	1
Quercetin	increases expression	1
T-2 Toxin	decreases expression, increases reaction, decreases reaction	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Cadmium Chloride	increases expression	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991711	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — *Science*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ERN2 across ~30M SureChEMBL compounds — explore on Sugi Predict.