Is EZH2 p.Ala487Thr (c.1459G>A) pathogenic?

EZH2 p.Ala487Thr (c.1459G>A) is classified Benign/Likely benign in EZH2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0618); Rare (popmax 0.801%, sas); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Ala487Thr (c.1459G>A)?

EZH2 p.Ala487Thr (c.1459G>A) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Ala487Thr (c.1459G>A) in the general population?

EZH2 p.Ala487Thr (c.1459G>A) is rare (popmax 0.801%, sas) (gnomAD).

What do computational predictors say about EZH2 p.Ala487Thr (c.1459G>A)?

AlphaMissense predicts likely benign (score 0.0618) — an in-silico prediction, not a clinical call.

EZH2 p.Ala487Thr

c.1459G>A · rs201135441 · VCV134222

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0618 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.801%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Weaver syndrome

Computational evidence

Protein change
AlphaMissense	0.0618	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.00	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 3.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 9,905 bp · p 5.7e-11 · regional, not allelic
Overall
CADD	20.6	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 A482T vs ClinVar A487T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.801% South Asian · 730/91,080 alleles

Filtering AF 0.753% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.734%

Overall 0.0483% 780/1,614,098 alleles · rare exomes 745/1,461,780 · genomes 35/152,318 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.801%	125
Remaining individualsnot grpmax-eligible	0.0544%	1,838
African / African-American	0.00533%	18,764
European (non-Finnish)	0.00102%	98,330

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.Ala487Thr
Coding: c.1459G>A
MANE Select: NM_004456
dbSNP: rs201135441
Type: single nucleotide variant
Location: chr7:148816730 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 482 UniProt numbering: 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.Ala487Val Uncertain significance ★ ⚠ same residue
EZH2 p.Ala487= Likely benign ★ 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

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-ala487thr (accessed [today's date]).

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