Is EZH2 p.Arg78Cys (c.232C>T) pathogenic?

EZH2 p.Arg78Cys (c.232C>T) is classified Benign in EZH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-02). AlphaMissense: likely benign (0.2781); Ultra-rare (popmax 0.012%, afr); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Arg78Cys (c.232C>T)?

EZH2 p.Arg78Cys (c.232C>T) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Arg78Cys (c.232C>T) in the general population?

EZH2 p.Arg78Cys (c.232C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about EZH2 p.Arg78Cys (c.232C>T)?

AlphaMissense predicts likely benign (score 0.2781) — an in-silico prediction, not a clinical call.

EZH2 p.Arg78Cys

c.232C>T · rs141583753 · VCV846780

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Weaver syndrome

Computational evidence

Protein change
AlphaMissense	0.2781	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Pangolin	Δ0.21	gain · loss 0.14 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 15 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	31.0	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 0.012% African / African-American · 9/74,834 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00062% 10/1,613,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,315
European (non-Finnish)	8.48e-05%	1,179,622

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.Arg78Cys
Coding: c.232C>T
MANE Select: NM_004456
dbSNP: rs141583753
Type: single nucleotide variant
Location: chr7:148846484 (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.Arg78= Likely 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-arg78cys (accessed [today's date]).

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