Is EZH2 p.Pro577Leu (c.1730C>T) pathogenic?

EZH2 p.Pro577Leu (c.1730C>T) is classified Likely pathogenic in EZH2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-01-18). AlphaMissense: likely pathogenic (0.9956); Very rare (popmax 8.47e-05%, nfe).

How common is EZH2 p.Pro577Leu (c.1730C>T) in the general population?

EZH2 p.Pro577Leu (c.1730C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EZH2 p.Pro577Leu (c.1730C>T)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

EZH2 p.Pro577Leu

c.1730C>T · rs1554486390 · VCV432410

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9956	likely pathogenic ✓ concordant with ClinVar
REVEL	0.722	pathogenic-leaning
SaProt	LLR -11.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 9,065 bp · p 2.2e-34 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P572L vs ClinVar P577L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 6.84e-05% 1/1,461,878 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.Pro577Leu
Coding: c.1730C>T
MANE Select: NM_004456
dbSNP: rs1554486390
Type: single nucleotide variant
Location: chr7:148814080 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 577: the cxc domain

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

Similar variants

EZH2 p.Pro577= Benign/Likely benign ★★ same residue
EZH2 p.Arg684Cys Pathogenic ★★ same type
EZH2 p.Glu745Lys Pathogenic/Likely pathogenic ★★ same type
EZH2 p.Ser695Leu Pathogenic/Likely pathogenic ★★ same type
EZH2 p.Tyr133Cys Pathogenic/Likely pathogenic ★★ same type
EZH2 p.Tyr741His Likely pathogenic ★★ same type
EZH2 p.Val626Met Pathogenic ★★ same type
EZH2 p.Val679Leu Likely pathogenic ★★ same type

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-pro577leu (accessed [today's date]).

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