Is EZH2 p.Ala342Pro (c.1024G>C) pathogenic?

EZH2 p.Ala342Pro (c.1024G>C) is classified Uncertain significance in EZH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-31). AlphaMissense: likely pathogenic (0.749); Absent from gnomAD v4.1; Associated with Weaver syndrome.

What condition is associated with EZH2 p.Ala342Pro (c.1024G>C)?

EZH2 p.Ala342Pro (c.1024G>C) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Ala342Pro (c.1024G>C) in the general population?

EZH2 p.Ala342Pro (c.1024G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EZH2 p.Ala342Pro (c.1024G>C)?

AlphaMissense predicts likely pathogenic (score 0.749) — an in-silico prediction, not a clinical call.

EZH2 p.Ala342Pro

c.1024G>C · rs2129471845 · VCV2800781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.749 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Weaver syndrome

Computational evidence

Protein change
AlphaMissense	0.749	likely pathogenic
REVEL	0.372	indeterminate
SaProt	LLR -10.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 9,905 bp · p 5.7e-11 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A337P vs ClinVar A342P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EZH2
Protein: p.Ala342Pro
Coding: c.1024G>C
MANE Select: NM_004456
dbSNP: rs2129471845
Type: single nucleotide variant
Location: chr7:148818093 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 337 UniProt numbering: the 'interaction with dnmt1, dnmt3a and dnmt3b' region; the 'interaction with cdyl' 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.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
EZH2 c.626-3T>C Uncertain significance ★★ same condition
EZH2 p.Ala255Val Uncertain significance ★★ ⚠ 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-ala342pro (accessed [today's date]).

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