Is EZH2 p.Leu252Phe (c.754C>T) pathogenic?

EZH2 p.Leu252Phe (c.754C>T) is classified Uncertain significance in EZH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-11). AlphaMissense: likely benign (0.2522); Very rare (popmax 8.74e-05%, nfe); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Leu252Phe (c.754C>T)?

EZH2 p.Leu252Phe (c.754C>T) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Leu252Phe (c.754C>T) in the general population?

EZH2 p.Leu252Phe (c.754C>T) is very rare (popmax 8.74e-05%, nfe) (gnomAD).

What do computational predictors say about EZH2 p.Leu252Phe (c.754C>T)?

AlphaMissense predicts likely benign (score 0.2522) — an in-silico prediction, not a clinical call.

EZH2 p.Leu252Phe

c.754C>T · rs2129475548 · VCV1416257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.74e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Weaver syndrome

Computational evidence

Protein change
AlphaMissense	0.2522	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP -0.22, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 9,905 bp · p 5.7e-11 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.74e-05% European (non-Finnish) · 1/1,144,208 alleles

Overall 7.16e-05% 1/1,395,758 alleles · very rare

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.Leu252Phe
Coding: c.754C>T
MANE Select: NM_004456
dbSNP: rs2129475548
Type: single nucleotide variant
Location: chr7:148826607 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 252: the 'interaction with dnmt1, dnmt3a and dnmt3b' 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-leu252phe (accessed [today's date]).

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