Is EZH2 p.Asp185= (c.555C>T) pathogenic?

EZH2 p.Asp185= (c.555C>T) is classified Likely benign in EZH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-29). Rare (popmax 0.1%, eas); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Asp185= (c.555C>T)?

EZH2 p.Asp185= (c.555C>T) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Asp185= (c.555C>T) in the general population?

EZH2 p.Asp185= (c.555C>T) is rare (popmax 0.1%, eas) (gnomAD).

EZH2 p.Asp185=

c.555C>T · rs555589547 · VCV1140536

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Conditions

Weaver syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.6	GERP -3.4
Overall
CADD	0.991	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.1% East Asian · 45/44,828 alleles

Filtering AF 0.0771% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0689%

Overall 0.0031% 50/1,612,874 alleles · rare exomes 47/1,461,318 · genomes 3/151,556 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	996
South Asian	0.0033%	30,321
European (non-Finnish)	0.00017%	589,810

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.Asp185=
Coding: c.555C>T
MANE Select: NM_004456
dbSNP: rs555589547
Type: single nucleotide variant
Location: chr7:148828810 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 185: the 'interaction with dnmt1, dnmt3a and dnmt3b' region; a UniProt-annotated variant site (decreased histone methyltransferase activity); 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.Asp185His Benign ★★ ⚠ 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
EZH2 c.626-3T>C 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-asp185 (accessed [today's date]).

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