# NM_004456.5(EZH2):c.1689G>T (p.Pro563=)

https://sugi.bio/variant/ezh2-p-pro563

## Summary

**EZH2 p.Pro563= (c.1689G>T)** is classified **Likely benign** in EZH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). Very rare (popmax 0.00127%, nfe); Associated with Weaver syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs144723981 · 1 submitter · 1 linked condition · very rare (popmax 0.00127%, nfe)

## For patients & families {#patients}

This is a change in the EZH2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Weaver syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007878/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EZH2](https://sugi.bio/atlas/gene/EZH2/) |
| Protein change (HGVS p.) | p.Pro563= |
| Coding change (HGVS c.) | c.1689G>T |
| MANE Select transcript | [NM_004456](https://www.ncbi.nlm.nih.gov/nuccore/NM_004456) |
| dbSNP | [rs144723981](https://www.ncbi.nlm.nih.gov/snp/rs144723981/) |
| Variant type | single nucleotide variant |
| Location | chr7:148814121-148814121 (GRCh38) |
| ClinVar | [VCV2062926](https://www.ncbi.nlm.nih.gov/clinvar/variation/2062926/) |

**All HGVS expressions:** `LRG_531:g.75229G>T`, `LRG_531t1:c.1689G>T`, `NC_000007.13:g.148511213C>A`, `NC_000007.14:g.148814121C>A`, `NG_032043.1:g.75229G>T`, `NM_001203247.2:c.1674G>T`, `NM_001203248.2:c.1647G>T`, `NM_001203249.2:c.1521G>T`, `NM_004456.5:c.1689G>T`, `NM_152998.3:c.1557G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -5.704, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 2.208**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.85 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00127%** (nfe) · FAF95 0.000763% · FAF99 0.000605% · 15/1,179,712 in the highest group · 15/1,612,990 alleles overall — very rare (popmax 0.00127%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**EZH2** population constraint: LOEUF 0.272, pLI 1, missense-Z 5.1188. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Weaver syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **563** lies in the cxc domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 76.58, 43% of residues very-high.

**41 experimental structure(s)** (PDB): [4MI0](https://www.rcsb.org/structure/4MI0), [4MI5](https://www.rcsb.org/structure/4MI5), [5GSA](https://www.rcsb.org/structure/5GSA), [5H14](https://www.rcsb.org/structure/5H14), [5H15](https://www.rcsb.org/structure/5H15), [5H17](https://www.rcsb.org/structure/5H17) — incl. mutant structure 5IJ8.

## What this gene does {#gene-function}

*Describes the biological roles of EZH2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** EZH2's established molecular role includes transcription corepressor binding. p.Pro563= falls in the cxc domain. In Reactome, EZH2 is annotated in disease pathway(s) including **Defective pyroptosis**, **HCMV Early Events**.

**Disease mechanism (Reactome):** EZH2 loss or alteration is curated in [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421), [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690).

### Pathways affected {#pathways}

EZH2 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421) | curated |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [PRC2 methylates histones and DNA](https://reactome.org/content/detail/R-HSA-212300) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription corepressor binding, chromatin binding, RNA binding, protein-lysine N-methyltransferase activity, chromatin DNA binding, nucleosome binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of cell population proliferation, positive regulation of epithelial to mesenchymal transition, positive regulation of cell migration, regulatory ncRNA-mediated heterochromatin formation, heterochromatin formation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-24.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-24 |

## Associated conditions {#conditions}

[Weaver syndrome](https://sugi.bio/atlas/disease/weaver-syndrome/).

**Reported phenotype names (ClinVar):** Weaver syndrome, Weaver Smith syndrome, Overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly.

## Similar variants {#similar}

Related EZH2 variant pages (same residue, condition, or type): [EZH2 p.Pro563Leu](/variant/ezh2-p-pro563leu), [EZH2 p.Arg684Cys](/variant/ezh2-p-arg684cys), [EZH2 p.Glu745Lys](/variant/ezh2-p-glu745lys), [EZH2 p.Ser695Leu](/variant/ezh2-p-ser695leu), [EZH2 p.Tyr133Cys](/variant/ezh2-p-tyr133cys), [EZH2 p.Val626Met](/variant/ezh2-p-val626met), [EZH2 p.Val679Leu](/variant/ezh2-p-val679leu), [EZH2 c.626-3T>C](/variant/ezh2-c-626-minus-3t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2062926). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*