Is EZH2 p.Pro115Ala (c.343C>G) pathogenic?

EZH2 p.Pro115Ala (c.343C>G) is classified Uncertain significance in EZH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-10). AlphaMissense: likely pathogenic (0.7375); Very rare (popmax 0.00168%, amr).

How common is EZH2 p.Pro115Ala (c.343C>G) in the general population?

EZH2 p.Pro115Ala (c.343C>G) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about EZH2 p.Pro115Ala (c.343C>G)?

AlphaMissense predicts likely pathogenic (score 0.7375) — an in-silico prediction, not a clinical call.

EZH2 p.Pro115Ala

c.343C>G · rs1324786734 · VCV1312083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7375	likely pathogenic
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,839 bp · p 5.6e-12 · regional, not allelic
Overall
CADD	24.6	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 0.00168% Admixed American · 1/59,418 alleles

Overall 6.27e-05% 1/1,595,058 alleles · very rare exomes 1/1,442,802 · genomes 0/152,256 · joint denominator

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.Pro115Ala
Coding: c.343C>G
MANE Select: NM_004456
dbSNP: rs1324786734
Type: single nucleotide variant
Location: chr7:148832654 (GRCh38)
Gene constraint: LOEUF 0.272 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.58 · 41 PDB
Residue 115: the 'interaction with dnmt1, dnmt3a and dnmt3b' region

Full EZH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EZH2 p.Arg684Cys Pathogenic ★★ same type
EZH2 p.Glu745Lys Pathogenic/Likely pathogenic ★★ same type
EZH2 p.Ser695Leu Pathogenic/Likely pathogenic ★★ same type
EZH2 p.Tyr133Cys Pathogenic/Likely pathogenic ★★ same type
EZH2 p.Tyr741His Likely pathogenic ★★ same type
EZH2 p.Val626Met Pathogenic ★★ same type
EZH2 p.Val679Leu Likely pathogenic ★★ same type
EZH2 c.626-3T>C Uncertain significance ★★ same type

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-pro115ala (accessed [today's date]).

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