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)

Definitive · Weaver syndrome · AD · ClinGen 2022

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

1192

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

Background carrier burden — how many people carry a rare variant somewhere in EZH2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

512 rare PASS variants

Rare truncating (LoF)

1 in 7,800

42 rare PASS variants

Rare synonymous (reference)

1 in 130

361 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EZH2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 220	1 in 6,000
South Asian	~43k	1 in 390	≈ 1 in 36,000
Remaining (unassigned)	~30k	1 in 200	≈ 1 in 15,000
European (Finnish)	~27k	1 in 600	≈ 1 in 27,000
Admixed American	~22k	1 in 270	≈ 1 in 8,700
African / African American	~21k	1 in 230	1 in 2,800
East Asian	~20k	1 in 690	none seen
Ashkenazi Jewish	~13k	1 in 590	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 290	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 16 of 19 coding exons well covered in gnomAD exomes; exons 4, 5, 8 marginal. Genomes: all 19.? see exons ↓

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

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

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

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