Is EZH2 p.Asp191= (c.573C>T) pathogenic?

EZH2 p.Asp191= (c.573C>T) is classified Likely benign in EZH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). Ultra-rare (popmax 0.0165%, mid); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Asp191= (c.573C>T)?

EZH2 p.Asp191= (c.573C>T) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Asp191= (c.573C>T) in the general population?

EZH2 p.Asp191= (c.573C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

EZH2 p.Asp191=

c.573C>T · rs377682721 · VCV699611

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -0.076	GERP -2, phastCons 0.015
Overall
CADD	8.726	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00576% 93/1,613,376 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.00703%	14,215
Remaining individualsnot grpmax-eligible	0.0064%	15,623
Admixed American	0.00334%	29,970
African / African-American	0.00267%	37,448
South Asian	0.0011%	91,028

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.Asp191=
Coding: c.573C>T
MANE Select: NM_004456
dbSNP: rs377682721
Type: single nucleotide variant
Location: chr7:148828792 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 191: the 'interaction with dnmt1, dnmt3a and dnmt3b' region; the 'disordered' region

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-asp191 (accessed [today's date]).

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