Is EZH2 p.Ile744= (c.2232C>T) pathogenic?

EZH2 p.Ile744= (c.2232C>T) is classified Likely benign in EZH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-14). Very rare (popmax 0.00682%, sas); Associated with Weaver syndrome.

What condition is associated with EZH2 p.Ile744= (c.2232C>T)?

EZH2 p.Ile744= (c.2232C>T) is associated with Weaver syndrome (ClinVar).

How common is EZH2 p.Ile744= (c.2232C>T) in the general population?

EZH2 p.Ile744= (c.2232C>T) is very rare (popmax 0.00682%, sas) (gnomAD).

EZH2 p.Ile744=

c.2232C>T · rs373975096 · VCV384018

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00682%, sas)

Conditions

Weaver syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.75	GERP -2.8
Overall
CADD	7.569	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00682% South Asian · 6/87,948 alleles

Filtering AF 0.00295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00201%

Overall 0.00213% 34/1,598,100 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00682%	14,658
Remaining individualsnot grpmax-eligible	0.00323%	30,955
African / African-American	0.00268%	37,329
European (non-Finnish)	0.00205%	48,822

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.Ile744=
Coding: c.2232C>T
MANE Select: NM_004456
dbSNP: rs373975096
Type: single nucleotide variant
Location: chr7:148807670 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 744: a UniProt-annotated variant site (in wvs)

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.Ile744_Glu745insIle Uncertain significance ★ 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
EZH2 c.626-3T>C 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-ile744 (accessed [today's date]).

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