Is EZH2 p.Val742= (c.2226C>T) pathogenic?

EZH2 p.Val742= (c.2226C>T) is classified Likely benign in EZH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). Ultra-rare (popmax 0.0576%, afr); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Val742= (c.2226C>T)?

EZH2 p.Val742= (c.2226C>T) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Val742= (c.2226C>T) in the general population?

EZH2 p.Val742= (c.2226C>T) is ultra-rare (popmax 0.0576%, afr) (gnomAD).

EZH2 p.Val742=

c.2226C>T · rs148228353 · VCV416830

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0576%, afr)

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
Pangolin	Δ0.20	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.9	GERP -1.1, phastCons 1
Overall
CADD	12.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0576% African / African-American · 43/74,666 alleles

Filtering AF 0.0439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0391%

Overall 0.00995% 159/1,597,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0576%	1,736
Remaining individualsnot grpmax-eligible	0.00969%	10,316
European (non-Finnish)	0.00888%	11,265
Admixed American	0.00345%	29,013
South Asian	0.00341%	29,316
East Asian	0.00225%	44,538

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.Val742=
Coding: c.2226C>T
MANE Select: NM_004456
dbSNP: rs148228353
Type: single nucleotide variant
Location: chr7:148807676 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 742: a UniProt-annotated variant site (in wvs)

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.Val742Ala 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
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-val742 (accessed [today's date]).

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