EZH2

Chr 7AD

enhancer of zeste 2 polycomb repressive complex 2 subunit

Also known as: ENX-1, ENX1, EZH2b, KMT6, KMT6A, WVS, WVS2

NCBI Gene: 2146ENSG00000106462UniProt: Q15910

This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein associates with the embryonic ectoderm development protein, the VAV1 oncoprotein, and the X-linked nuclear protein. This protein may play a role in the hematopoietic and central nervous systems. Multiple alternatively splcied transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Feb 2011]

Primary Disease Associations & Inheritance

Weaver syndromeMIM #277590
AD
564
ClinVar variants
45
Pathogenic / LP
1.00
pLI score· haploinsufficient
12
Active trials
Clinical Summary— EZH2
🧬
Gene-Disease Validity (ClinGen)
Weaver syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
45 Pathogenic / Likely Pathogenic· 208 VUS of 564 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.15LOEUF
pLI 1.000
Z-score 5.81
OE 0.05 (0.02–0.15)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
4.68Z-score
OE missense 0.36 (0.32–0.41)
154 obs / 425.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.05 (0.02–0.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.36 (0.32–0.41)
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.1.12
0≤1.21.6
LoF obs/exp: 2 / 43.2Missense obs/exp: 154 / 425.8Syn Z: -1.18

ClinVar Variant Classifications

564 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic20
VUS208
Likely Benign259
Benign44
Conflicting8
25
Pathogenic
20
Likely Pathogenic
208
VUS
259
Likely Benign
44
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
24
0
25
Likely Pathogenic
2
15
3
0
20
VUS
12
154
39
3
208
Likely Benign
0
14
138
107
259
Benign
0
5
35
4
44
Conflicting
—8
Total14189239114564

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

View in ClinVar →

Protein Context — Lollipop Plot

EZH2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

EZH2-related Weaver syndrome

definitive
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Weaver syndrome

MIM #277590

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — EZH2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
EZH2: a novel target for cancer treatment.
Duan R et al.·J Hematol Oncol
2020Review
Targeting EZH2 in cancer.
Kim KH et al.·Nat Med
2016Review
EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.
Verma A et al.·Nat Commun
2022
The roles of EZH2 in cancer and its inhibitors.
Liu Y et al.·Med Oncol
2023Review
Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.
Ku SY et al.·Science
2017
Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors.
Huang X et al.·Cell
2018
Ezh2 Shapes T Cell Plasticity to Drive Atherosclerosis.
Bonfiglio CA et al.·Circulation
2025
EZH2-Myc driven glioblastoma elicited by cytomegalovirus infection of human astrocytes.
El Baba R et al.·Oncogene
2023
EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation.
Wang L et al.·Nat Commun
2022
An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer.
Davies A et al.·Nat Cell Biol
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Acetylated Nanoformulation of N-(4-Hydroxyphenyl)-4-Oxoretinamide Inhibits EZH2-Mediated Epigenetic Repression in Neuroblastoma.
Mrunalini B et al.·Small
2026
Knockdown of SOX4 attenuates sepsis myocardial injury by inhibiting the EZH2/H3K27me3/SOCS3 axis.
Zhao H et al.·Mamm Genome
2026
Chronic Hypoxia Disrupts Spermatogenesis Through ASXL2-EZH2-Mediated Microtubule Destabilization.
Yin J et al.·Adv Sci (Weinh)
2026
EZH2 inhibition overcomes immune evasion in lung adenocarcinoma by restoring CCL5-mediated T-cell recruitment and MHC class I antigen presentation.
Lin Q et al.·Acta Biochim Biophys Sin (Shanghai)
2026
RBMX Transcriptionally Repressed by EZH2-Associated H3K27me3 Modification Attenuates Pyroptosis in Renal Ischemia/Reperfusion Injury via Regulating SIRT3/NLRP3 Inflammasome Activation.
Wang YH et al.·Kaohsiung J Med Sci
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Peripheral T-Cell Lymphoma

Real-world Outcomes of Peripheral T-cell Lymphoma: A Multicenter Retrospective and Prospective Cohort Study

RECRUITING
NCT07270861Fudan UniversityStarted 2025-11-15
Observational
Lymphoma, Follicular

A Study of Tazemetostat on Safety in Participants With Relapsed or Refractory Follicular Lymphoma With Enhancer of Zeste Homolog 2 (EZH2) Gene Mutation in Japan

ACTIVE NOT RECRUITING
NCT05228158Eisai Co., Ltd.Started 2021-08-16
Tazemetostat
Myeloproliferative Neoplasm

Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)

RECRUITING
NCT06022328University Hospital, BordeauxStarted 2023-12-15
Assessment of the epigenetic age
AMLMDS

Molecular Genetics Guide the Maintenance Therapy After Allogeneic Hematopoietic Stem Cell Transplantation

RECRUITING
NCT06972641Phase PHASE2, PHASE3Ruijin HospitalStarted 2025-06-10
DecitabineSorafenib (BAY-43-9006)，giritinibAvastinib
Locally Advanced Urothelial CarcinomaMetastatic Urothelial CarcinomaStage III Bladder Cancer AJCC v8

Testing the Addition of Tazemetostat to the Immunotherapy Drug, Pembrolizumab (MK-3475), in Advanced Urothelial Carcinoma

ACTIVE NOT RECRUITING
NCT03854474Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2019-11-18
Biospecimen CollectionComputed TomographyMagnetic Resonance Imaging
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies
Peripheral T Cells Lymphoma (PTCL)

Zeprumetostat, Azacitidine Combined With Lipo-MIT in R/R PTCL

RECRUITING
NCT07372352Phase PHASE2The First Affiliated Hospital of Soochow UniversityStarted 2026-01-15
ZeprumetostatAzacitidine (AZA)Mitoxantrone Hydrochloride Liposome
Gastric and Cardia Adenocarcinomas

Biomoleculars Markers of Sensitivity to Pre- and Post-operative Chemotherapy of Gastric and Cardia Adenocarcinomas: a Pilot Study

RECRUITING
NCT02491840Phase NAUniversity Hospital, Strasbourg, FranceStarted 2016-05
Biopsy
Recurrent B-Cell Non-Hodgkin LymphomaRecurrent Diffuse Large B-Cell Lymphoma Germinal Center B-Cell TypeRecurrent Follicular Lymphoma

Testing the Safety of the Anti-cancer Drugs Tazemetostat and Belinostat in Patients With Lymphomas That Have Resisted Treatment

RECRUITING
NCT05627245Phase PHASE1National Cancer Institute (NCI)Started 2023-03-01
BelinostatBiopsy ProcedureBiospecimen Collection
Advanced Malignant Solid NeoplasmAnn Arbor Stage III Non-Hodgkin LymphomaAnn Arbor Stage IV Non-Hodgkin Lymphoma

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT03155620Phase PHASE2National Cancer Institute (NCI)Started 2017-07-31
Biopsy ProcedureBiospecimen CollectionBone Marrow Aspiration and Biopsy
Solid Tumor MalignanciesClear Cell Endometrial CarcinomaOvarian Cancer

Efficacy and Safety of the Valemetostat in Patients With Selected Solid Tumors.

NOT YET RECRUITING
NCT07303387Phase PHASE2Gustave Roussy, Cancer Campus, Grand ParisStarted 2026-02-28
Valemetostat Tosylate
Clinical Stage IV Cutaneous Melanoma AJCC v8Metastatic Melanoma

Testing the Addition of the Anti-cancer Drug, Tazemetostat, to the Usual Treatment (Dabrafenib and Trametinib) for Metastatic Melanoma That Has Progressed on the Usual Treatment

ACTIVE NOT RECRUITING
NCT04557956Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2021-08-19
Biopsy ProcedureComputed TomographyDabrafenib Mesylate

External Resources

Links to major genomics databases and tools