Is EZH2 p.Ser519Pro (c.1555T>C) pathogenic?

EZH2 p.Ser519Pro (c.1555T>C) is classified Conflicting classifications of pathogenicity in EZH2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-25). AlphaMissense: likely benign (0.2398); Very rare (popmax 0.00347%, nfe); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Ser519Pro (c.1555T>C)?

EZH2 p.Ser519Pro (c.1555T>C) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Ser519Pro (c.1555T>C) in the general population?

EZH2 p.Ser519Pro (c.1555T>C) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about EZH2 p.Ser519Pro (c.1555T>C)?

AlphaMissense predicts likely benign (score 0.2398) — an in-silico prediction, not a clinical call.

EZH2 p.Ser519Pro

c.1555T>C · rs747009766 · VCV359279

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Weaver syndrome

Computational evidence

Protein change
AlphaMissense	0.2398	likely benign
REVEL	0.769	pathogenic-leaning
SaProt	LLR -7.65	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	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	30.0	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 S514P vs ClinVar S519P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% European (non-Finnish) · 41/1,179,904 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00273% 44/1,613,790 alleles · very rare exomes 40/1,461,576 · genomes 4/152,214 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,823
European (non-Finnish)grpmax	0.00347%	28,778

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser519Pro
Coding: c.1555T>C
MANE Select: NM_004456
dbSNP: rs747009766
Type: single nucleotide variant
Location: chr7:148815031 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 514 UniProt numbering: the cxc domain; the 'interaction with cdyl' 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-ser519pro (accessed [today's date]).

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