Is EZH2 p.Pro132= (c.396T>C) pathogenic?

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.

What condition is associated with EZH2 p.Pro132= (c.396T>C)?

EZH2 p.Pro132= (c.396T>C) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Pro132= (c.396T>C) in the general population?

EZH2 p.Pro132= (c.396T>C) is rare (popmax 0.611%, nfe) (gnomAD).

EZH2 p.Pro132=

c.396T>C · rs61732845 · VCV359286

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.611%, nfe)

Conditions

Weaver syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.55, phastCons 1
Overall
CADD	8.292	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.611% European (non-Finnish) · 7,143/1,169,504 alleles

Filtering AF 0.599% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.594%

Overall 0.575% 9,181/1,596,652 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.36%	74
Finnishnot grpmax-eligible	1.13%	88
Remaining individualsnot 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
Amishnot grpmax-eligible	0.11%	912
African / African-American	0.0968%	1,033

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EZH2
Protein: p.Pro132=
Coding: c.396T>C
MANE Select: NM_004456
dbSNP: rs61732845
Type: single nucleotide variant
Location: chr7:148829816 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 132: a UniProt-annotated variant site (in wvs; decreased histone methyltransferase activity); the 'interaction with dnmt1, dnmt3a and dnmt3b' region; an α-helix

Full EZH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Weaver syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EZH2 p.Pro132Ser Pathogenic same residue
EZH2 p.Pro132Thr Likely pathogenic ★ same residue
EZH2 p.Arg684Cys Pathogenic ★★ same condition
EZH2 p.Glu745Lys Pathogenic/Likely pathogenic ★★ same condition
EZH2 p.Ser695Leu Pathogenic/Likely pathogenic ★★ same condition
EZH2 p.Tyr133Cys Pathogenic/Likely pathogenic ★★ same condition
EZH2 p.Val626Met Pathogenic ★★ same condition
EZH2 p.Val679Leu Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ezh2-p-pro132 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown