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: 2146 ENSG00000106462 UniProt: Q15910 OMIM: 601573

The protein serves as the catalytic subunit of the PRC2 complex, methylating histone H3 at lysine 27 to repress gene transcription, which is essential for embryonic development and stem cell identity. Mutations cause Weaver syndrome, characterized by overgrowth, intellectual disability, and distinctive facial features with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI ~1.0), reflecting its critical role in development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Weaver syndromeMIM #277590

Clinical highlights

Gene-disease validity (ClinGen)

Weaver syndrome · ADDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

1121

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.15

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — EZH2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.05 (0.02–0.15)

0≤0.351.4

Missense OE?0.36 (0.32–0.41)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 2 / 43.2Missense obs/exp: 154 / 425.8Syn Z: -1.18

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

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

📖

GeneReview available — EZH2

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Myeloproliferative Neoplasms

Registry of Patients With MPNs in Taiwan

ACTIVE NOT RECRUITING

NCT03618485Chang Gung Memorial HospitalStarted 2017-04-01

Solid Tumor MalignanciesClear Cell Endometrial CarcinomaOvarian Cancer

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

RECRUITING

NCT07303387Phase PHASE2Gustave Roussy, Cancer Campus, Grand ParisStarted 2026-03-05

Valemetostat Tosylate

PTCLRefractory

Genotype-guided Targeted Agents Plus EZH2i for Primary Refractory PTCL

NOT YET RECRUITING

NCT07493330Phase PHASE1, PHASE2Ruijin HospitalStarted 2026-03-23

Zeprumetostat+AzacitadineZeprumetostat+DecitabineZeprumetostat+Chidamide

Follicular Lymphoma

Multilayer Biological Characterization of Advanced Follicular Lymphoma: a Translational Study From FIL_FOLL12 Trial

RECRUITING

NCT05816850Fondazione Italiana Linfomi - ETSStarted 2023-09-19

EZH2 mutations/CNAs by droplet digital PCR (ddPCR)EZH2-derived gene expression signature by RNA-Seq

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

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

Chronic Myelomonocytic Leukemia

Relevance of Peripheral Cells in the Pathophysiology of Chronic Myelomonocytic Leukemia (CMML)

RECRUITING

NCT03280888Centre Hospitalier Universitaire de NiceStarted 2014-11-05

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

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

Chronic Myeloid Leukemia, Chronic PhaseWithdrawal;Drug

Efficacy and Safety of TKIs' Withdrawal After a Two-step Dose Reduction in Patients with Chronic Myeloid Leukemia

ACTIVE NOT RECRUITING

NCT04147533Phase PHASE2Masaryk UniversityStarted 2020-06-16

Imatinib withdrawalDasatinibNilotinib

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

Clinical Stage IV Cutaneous Melanoma AJCC v8Metastatic Melanoma

Testing the Addition of the Anti-cancer Drug, Tazemetostat, to (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

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Integrative study of EZH2 mutational status, copy number, protein expression and H3K27 trimethylation in AML/MDS patients

Stomper J et al.·Clin Epigenetics

2021Cohort