Is EZH2 p.Arg78= (c.234C>T) pathogenic?

EZH2 p.Arg78= (c.234C>T) is classified Likely benign in EZH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). Ultra-rare (popmax 0.0351%, amr); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Arg78= (c.234C>T)?

EZH2 p.Arg78= (c.234C>T) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Arg78= (c.234C>T) in the general population?

EZH2 p.Arg78= (c.234C>T) is ultra-rare (popmax 0.0351%, amr) (gnomAD).

EZH2 p.Arg78=

c.234C>T · rs140399505 · VCV359287

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, amr)

Conditions

Weaver syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Pangolin	Δ0.20	gain · loss 0.18 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 5.6	GERP 0.81, phastCons 1
Overall
CADD	16.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0351% Admixed American · 21/59,914 alleles

Filtering AF 0.026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.0235% 379/1,613,268 alleles · ultra-rare exomes 357/1,461,104 · genomes 22/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0351%	2,853
European (non-Finnish)	0.0285%	3,511
Remaining individualsnot grpmax-eligible	0.0192%	5,206
South Asian	0.0055%	18,186
African / African-American	0.004%	24,981
Finnishnot grpmax-eligible	0.00313%	31,992

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.Arg78=
Coding: c.234C>T
MANE Select: NM_004456
dbSNP: rs140399505
Type: single nucleotide variant
Location: chr7:148846482 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 78: the 'interaction with dnmt1, dnmt3a and dnmt3b' region; a β-strand

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.Arg78Cys Benign ★ same residue
EZH2 p.Arg78His 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-arg78 (accessed [today's date]).

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