NRG2

Chr 5

neuregulin 2

Also known as: DON1, HRG2, NTAK

NCBI Gene: 9542ENSG00000158458UniProt: O14511

This gene encodes a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ERBB family of receptors, this protein induces the growth and differentiation of epithelial, neuronal, glial, and other types of cells. The gene consists of 12 exons and the genomic structure is similar to that of neuregulin 1, another member of the neuregulin family of ligands. The products of these genes mediate distinct biological processes by acting at different sites in tissues and eliciting different biological responses in cells. This gene is located close to the region for demyelinating Charcot-Marie-Tooth disease locus, but is not responsible for this disease. Alternative transcript variants encoding distinct isoforms have been described. [provided by RefSeq, May 2010]

190
ClinVar variants
12
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NRG2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 164 VUS of 190 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.
0.21LOEUF
pLI 0.999
Z-score 4.70
OE 0.07 (0.03–0.21)
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 0.68 (0.62–0.76)
281 obs / 410.6 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.0.07 (0.03–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.62–0.76)
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.0.90
0≤1.21.6
LoF obs/exp: 2 / 29.6Missense obs/exp: 281 / 410.6Syn Z: 1.06

ClinVar Variant Classifications

190 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
VUS164
Likely Benign12
Benign1
Conflicting1
12
Pathogenic
164
VUS
12
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
0
0
0
0
0
VUS
1
159
4
0
164
Likely Benign
0
10
1
1
12
Benign
0
0
1
0
1
Conflicting
—1
Total1169181190

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

View in ClinVar →

Protein Context — Lollipop Plot

NRG2 · 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
NEUREGULIN 2; NRG2
MIM #603818 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
NRG1 and NRG2 fusions in non-small cell lung cancer (NSCLC): seven years between lights and shadows.
Trombetta D et al.·Expert Opin Ther Targets
2021
Upstream-binding protein-1 promotes breast tumorigenesis by inducing NRG2-mediated metastasis, plasticity, and macrophage polarization.
Jaiswal A et al.·Int J Biol Macromol
2025
Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome.
Hosoki K et al.·Am J Med Genet A
2012
Fine mapping of new glaucoma locus GLC1M and exclusion of neuregulin 2 as the causative gene.
Fan BJ et al.·Mol Vis
2007
Relationships between progesterone receptor isoforms and the HER/ErbB receptors and ligands network in 299 primary breast cancers.
Lindet C et al.·Int J Biol Markers
2012Review
ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms.
Arribas AJ et al.·Mol Cancer Ther
2024
Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington's Disease Status Based on Omics Data.
Christodoulou CC et al.·Int J Mol Sci
2020
YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression.
He C et al.·Oncogene
2015
Gene expression profiling of ERBB receptors and ligands in human transitional cell carcinoma of the bladder.
Amsellem-Ouazana D et al.·J Urol
2006
Transcriptomics and Prognosis Analysis to Identify Critical Biomarkers in Invasive Breast Carcinoma.
Wu J et al.·Technol Cancer Res Treat
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools