# NM_004456.5(EZH2):c.396T>C (p.Pro132=)

https://sugi.bio/variant/ezh2-p-pro132

## Summary

**EZH2 p.Pro132= (c.396T>C)** is classified **Benign/Likely benign** in EZH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-01). Rare (popmax 0.611%, nfe); Associated with Weaver syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs61732845 · 5 submitters · 1 linked condition · rare (popmax 0.611%, nfe)

## For patients & families {#patients}

This is a change in the EZH2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, 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.Pro132= |
| Coding change (HGVS c.) | c.396T>C |
| MANE Select transcript | [NM_004456](https://www.ncbi.nlm.nih.gov/nuccore/NM_004456) |
| dbSNP | [rs61732845](https://www.ncbi.nlm.nih.gov/snp/rs61732845/) |
| Variant type | single nucleotide variant |
| Location | chr7:148829816-148829816 (GRCh38) |
| ClinVar | [VCV359286](https://www.ncbi.nlm.nih.gov/clinvar/variation/359286/) |

**All HGVS expressions:** `LRG_531:g.59534T>C`, `LRG_531t1:c.396T>C`, `NC_000007.13:g.148526908A>G`, `NC_000007.14:g.148829816A>G`, `NG_032043.1:g.59534T>C`, `NM_001203247.2:c.396T>C`, `NM_001203248.2:c.369T>C`, `NM_001203249.2:c.369T>C`, `NM_004456.5:c.396T>C`, `NM_152998.3:c.279T>C`

## 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 2.055, GERP 0.546, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.292**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.611%** (nfe) · FAF95 0.599% · FAF99 0.594% · 7,143/1,169,504 in the highest group · 9,181/1,596,652 alleles overall — rare (popmax 0.611%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 1.36% | 74 |
| Finnish (not grpmax-eligible) | 1.13% | 88 |
| Remaining individuals (not grpmax-eligible) | 0.696% | 144 |
| European (non-Finnish) (grpmax) | 0.611% | 164 |
| Admixed American | 0.309% | 324 |
| South Asian | 0.261% | 383 |
| Middle Eastern | 0.149% | 670 |
| Amish (not grpmax-eligible) | 0.11% | 912 |
| African / African-American | 0.0968% | 1,033 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **132** lies in a UniProt-annotated variant site (in wvs; decreased histone methyltransferase activity); the 'interaction with dnmt1, dnmt3a and dnmt3b' region; an α-helix.

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.Pro132= falls in the interaction with dnmt1, dnmt3a and dnmt3b region. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (3 Benign, 2 Likely benign).

**Submission history:** 5 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-04-10 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Weaver syndrome, not provided, EZH2-related disorder, not specified, none provided, AllHighlyPenetrant, Weaver Smith syndrome, Overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly.

## Same-residue context {#hotspot}

Residue **132** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [EZH2 p.Pro132Ser](/variant/ezh2-p-pro132ser), [EZH2 p.Pro132Thr](/variant/ezh2-p-pro132thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EZH2 variant pages (same residue, condition, or type): [EZH2 p.Pro132Ser](/variant/ezh2-p-pro132ser), [EZH2 p.Pro132Thr](/variant/ezh2-p-pro132thr), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 359286). 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.*