Is EZH2 p.Arg46His (c.137G>A) pathogenic?

EZH2 p.Arg46His (c.137G>A) is classified Uncertain significance in EZH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-19). AlphaMissense: ambiguous (0.4141); Very rare (popmax 0.0011%, nfe); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Arg46His (c.137G>A)?

EZH2 p.Arg46His (c.137G>A) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Arg46His (c.137G>A) in the general population?

EZH2 p.Arg46His (c.137G>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about EZH2 p.Arg46His (c.137G>A)?

AlphaMissense predicts ambiguous (score 0.4141) — an in-silico prediction, not a clinical call.

EZH2 p.Arg46His

c.137G>A · rs1333628386 · VCV3251772

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Weaver syndrome

Computational evidence

Protein change
AlphaMissense	0.4141	ambiguous
REVEL	0.736	pathogenic-leaning
SaProt	LLR -8.26	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 15 kb · p 9.6e-05 · 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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,178,006 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00081% 13/1,604,438 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.Arg46His
Coding: c.137G>A
MANE Select: NM_004456
dbSNP: rs1333628386
Type: single nucleotide variant
Location: chr7:148846579 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 46: the 'interaction with dnmt1, dnmt3a and dnmt3b' region; the 'interaction with eed' region; an α-helix

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-arg46his (accessed [today's date]).

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