Is EZH2 p.Pro427= (c.1281A>G) pathogenic?

EZH2 p.Pro427= (c.1281A>G) is classified Benign/Likely benign in EZH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-16). Rare (popmax 0.178%, sas); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Pro427= (c.1281A>G)?

EZH2 p.Pro427= (c.1281A>G) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Pro427= (c.1281A>G) in the general population?

EZH2 p.Pro427= (c.1281A>G) is rare (popmax 0.178%, sas) (gnomAD).

EZH2 p.Pro427=

c.1281A>G · rs530239078 · VCV359282

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.178%, sas)

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 -0.74	GERP -2.7, phastCons 0.011
Overall
CADD	8.049	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.178% South Asian · 162/90,992 alleles

Filtering AF 0.156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.0104% 168/1,613,984 alleles · rare exomes 163/1,461,662 · genomes 5/152,322 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.178%	562
Remaining individualsnot grpmax-eligible	0.0064%	15,626
African / African-American	0.00133%	75,056
European (non-Finnish)	8.47e-05%	1,179,993

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.Pro427=
Coding: c.1281A>G
MANE Select: NM_004456
dbSNP: rs530239078
Type: single nucleotide variant
Location: chr7:148817351 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 427: 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-pro427 (accessed [today's date]).

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