ERN1

Chr 17

endoplasmic reticulum to nucleus signaling 1

Also known as: IRE1, IRE1P, IRE1a, hIRE1p

NCBI Gene: 2081ENSG00000178607UniProt: O75460

This gene encodes the transmembrane protein kinase inositol-requiring enzyme 1. The encoded protein contains two functional catalytic domains, a serine/threonine-protein kinase domain and an endoribonuclease domain. This protein functions as a sensor of unfolded proteins in the endoplasmic reticulum (ER) and triggers an intracellular signaling pathway termed the unfolded protein response (UPR). The UPR is an ER stress response that is conserved from yeast to mammals and activates genes involved in degrading misfolded proteins, regulating protein synthesis and activating molecular chaperones. This protein specifically mediates the splicing and activation of the stress response transcription factor X-box binding protein 1. [provided by RefSeq, Aug 2017]

0
Active trials
9
Pathogenic / LP
130
ClinVar variants
6
Pubs (1 yr)
2.3
Missense Z
0.29
LOEUF· LoF intolerant
Clinical Summary— ERN1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 111 VUS of 130 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.29LOEUF
pLI 0.990
Z-score 5.44
OE 0.16 (0.09–0.29)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.27Z-score
OE missense 0.73 (0.67–0.79)
413 obs / 564.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.16 (0.09–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.67–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 8 / 49.2Missense obs/exp: 413 / 564.5Syn Z: 0.25

ClinVar Variant Classifications

130 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
VUS111
Likely Benign7
Benign3
9
Pathogenic
111
VUS
7
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
0
0
0
VUS
0
108
3
0
111
Likely Benign
0
5
0
2
7
Benign
0
1
1
1
3
Total0114133130

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ERN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autophagy in age-related macular degeneration.
Kaarniranta K et al.·Autophagy
2023Review
New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD.
Larabi A et al.·Autophagy
2020Review
Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway.
Zheng ZG et al.·Autophagy
2021
ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer.
Strietz J et al.·Oncotarget
2016
Genetic contribution to cancer risk in patients with tooth loss: a genetic association study.
Bezamat M et al.·Sci Rep
2022Cohort
Potential biomarkers for inherited thrombocytopenia 2 identified by plasma proteomics.
Wang X et al.·Platelets
2022
Exercise's protective role in chronic obstructive pulmonary disease via modulation of M1 macrophage phenotype through the miR-124-3p/ERN1 axis.
Zeng H et al.·Sci Prog
2025
Polymorphism of salivary proteins and risk of periodontal diseases: A systematic review and meta-analysis of clinical studies.
Ahmad P et al.·J Dent
2024Meta-analysis
Intestinal NSD2 Aggravates Nonalcoholic Steatohepatitis Through Histone Modifications.
Zhang Y et al.·Adv Sci (Weinh)
2024
Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer's disease.
He L et al.·Transl Psychiatry
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Identification of an ERN1 target site within EGFP mRNA
Baeken MW et al.·J Cell Biochem
2022
Identification and verification of mitochondria-related genes biomarkers associated with immune infiltration for COPD using WGCNA and machine learning algorithms
Peng M et al.·Sci Rep
2025
The effects of ERN1 on gene expression during early rhizobial infection in Lotus japonicus
Liu M et al.·Front Plant Sci
2023
TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells
Bidooki SH et al.·Int J Mol Sci
2024
Inhibition of ERN1 affects the expression of TGIF1 and other homeobox gene expressions in U87MG glioblastoma cells.
Minchenko OH et al.·Arch Biochem Biophys
2024
Knockdown of ERN1 disturbs the expression of phosphoserine aminotransferase 1 and related genes in glioblastoma cells.
Minchenko OH et al.·Arch Biochem Biophys
2024
A Neutrophil Extracellular Traps-Related Gene Trait Revealed the Prospective Therapy Strategy of Coronary Atherosclerosis
Li Z et al.·J Inflamm Res
2024
ERN1 knockdown modifies the hypoxic regulation of homeobox gene expression in U87MG glioblastoma cells.
Krasnytska DA et al.·Endocr Regul
2024
Hcmv-miR-UL148D regulates the staurosporine-induced apoptosis by targeting the Endoplasmic Reticulum to Nucleus signaling 1(ERN1)
Pandeya A et al.·PLoS One
2022
Top 9 full-text resultsSearch PubTator3 ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients