Is EZH2 p.Ser40Thr (c.119G>C) pathogenic?

EZH2 p.Ser40Thr (c.119G>C) is classified Uncertain significance in EZH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-21). AlphaMissense: likely benign (0.0848); Very rare (popmax 0.000262%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EZH2 p.Ser40Thr (c.119G>C)?

EZH2 p.Ser40Thr (c.119G>C) is associated with Inborn genetic diseases (ClinVar).

How common is EZH2 p.Ser40Thr (c.119G>C) in the general population?

EZH2 p.Ser40Thr (c.119G>C) is very rare (popmax 0.000262%, nfe) (gnomAD).

What do computational predictors say about EZH2 p.Ser40Thr (c.119G>C)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

EZH2 p.Ser40Thr

c.119G>C · VCV3846969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 15 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	21.1	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 0.000262% European (non-Finnish) · 3/1,145,574 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,453,528 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.Ser40Thr
Coding: c.119G>C
MANE Select: NM_004456
Type: single nucleotide variant
Location: chr7:148846597 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 40: the 'interaction with dnmt1, dnmt3a and dnmt3b' region; the 'interaction with eed' region

Full EZH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EZH2 p.Ser40Gly Uncertain significance ★ ⚠ same residue
EZH2 p.Ala255Val Uncertain significance ★★ ⚠ same condition
EZH2 p.Arg34Gln Uncertain significance ★★ ⚠ same condition
EZH2 p.Arg712Lys Uncertain significance ★★ ⚠ same condition
EZH2 p.Asn416Asp Uncertain significance ★★ ⚠ same condition
EZH2 p.Gly394Ala Uncertain significance ★★ ⚠ same condition
EZH2 p.Asp136His Likely pathogenic ★ same condition
EZH2 p.Ala269Asp 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-ser40thr (accessed [today's date]).

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