HEY2

Chr 6

hes related family bHLH transcription factor with YRPW motif 2

Also known as: CHF1, GRIDLOCK, GRL, HERP1, HESR2, HRT2, bHLHb32

NCBI Gene: 23493ENSG00000135547UniProt: Q9UBP5

This gene encodes a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The encoded protein forms homo- or hetero-dimers that localize to the nucleus and interact with a histone deacetylase complex to repress transcription. Expression of this gene is induced by the Notch signal transduction pathway. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

80
ClinVar variants
18
Pathogenic / LP
0.89
pLI score
0
Active trials
Clinical Summary— HEY2
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
18 Pathogenic / Likely Pathogenic· 55 VUS of 80 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.41LOEUF
pLI 0.893
Z-score 2.89
OE 0.09 (0.03–0.41)
Moderately constrained

More LoF-intolerant than ~75% 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.
0.85Z-score
OE missense 0.84 (0.74–0.95)
182 obs / 217.4 exp
Tolerant

Mild missense constraint

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.0.09 (0.03–0.41)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.74–0.95)
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.0.96
0≤1.21.6
LoF obs/exp: 1 / 11.7Missense obs/exp: 182 / 217.4Syn Z: 0.31

ClinVar Variant Classifications

80 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic2
VUS55
Likely Benign3
Benign4
16
Pathogenic
2
Likely Pathogenic
55
VUS
3
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
15
0
16
Likely Pathogenic
0
0
2
0
2
VUS
1
48
6
0
55
Likely Benign
0
2
0
1
3
Benign
0
0
3
1
4
Total15126280

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

View in ClinVar →

Protein Context — Lollipop Plot

HEY2 · 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 Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.
van Walree ES et al.·Genet Med
2021Meta-analysis
HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma.
Wu DC et al.·Oncotarget
2016
Recent understanding of clinical sequencing and gene-based risk stratification in inherited primary arrhythmia syndrome.
Aiba T·J Cardiol
2019Review
Loss of myocardial Hey2/Hrt2 function disrupts rightward shift of atrioventricular cushion tissue and causes tricuspid atresia.
Okumura K et al.·Dev Dyn
2024
Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome.
Fischer A et al.·Mamm Genome
2004Cohort
A Novel Somatic Variant in HEY2 Unveils an Alternative Splicing Isoform Linked to Ventricular Septal Defect.
Fardoun M et al.·Pediatr Cardiol
2019
Molecular Pathways and Animal Models of Tricuspid Atresia and Univentricular Heart.
Shibbani K et al.·Adv Exp Med Biol
2024Review
microRNA-599 promotes apoptosis and represses proliferation and epithelial-mesenchymal transition of papillary thyroid carcinoma cells via downregulation of Hey2-depentent Notch signaling pathway.
Wang DP et al.·J Cell Physiol
2020
CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling.
Zeng JS et al.·Int J Biochem Cell Biol
2018
Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current.
Nakano Y et al.·Circ Arrhythm Electrophysiol
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A novel heterozygous pathogenic variant in HEY2 led to a familial form of non-syndromic Tetralogy of Fallot.
Bergès C et al.·Eur J Hum Genet
2025
Super-enhancers and Mef2c: Novel regulators of cardiac hypertrophy via the Hey2/Notch/p38 signaling pathway.
Wang R et al.·Eur J Pharmacol
2025
The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.
She P et al.·Nat Commun
2025🔓 Open Access
MicroRNA-181b-5p/HEY2 axis is involved in the progress of deep venous thrombosis via mediating vascular endothelial injury.
Zhang D et al.·Hematology
2024
Hey2 enhancer activity defines unipotent progenitors for left ventricular cardiomyocytes in juxta-cardiac field of early mouse embryo.
Watanabe Y et al.·Proc Natl Acad Sci U S A
2023🔓 Open AccessFunctional
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