Is EZH1 p.Pro332Arg (c.995C>G) pathogenic?

EZH1 p.Pro332Arg (c.995C>G) is classified Uncertain significance in EZH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-28). AlphaMissense: likely pathogenic (0.7692); Very rare (popmax 0.00263%, nfe).

How common is EZH1 p.Pro332Arg (c.995C>G) in the general population?

EZH1 p.Pro332Arg (c.995C>G) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about EZH1 p.Pro332Arg (c.995C>G)?

AlphaMissense predicts likely pathogenic (score 0.7692) — an in-silico prediction, not a clinical call.

EZH1 p.Pro332Arg

c.995C>G · VCV4840728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7692	likely pathogenic
REVEL	0.751	pathogenic-leaning
SaProt	LLR -12.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 7,221 bp · p 2e-11 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,180,026 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00192% 31/1,614,176 alleles · very rare exomes 31/1,461,852 · genomes 0/152,324 · 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: EZH1
Protein: p.Pro332Arg
Coding: c.995C>G
MANE Select: NM_001991
Type: single nucleotide variant
Location: chr17:42718004 (GRCh38)
Gene constraint: LOEUF 0.439 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.05 · 4 PDB

Full EZH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EZH1 p.Ala678Gly Pathogenic/Likely pathogenic ★★ same type
EZH1 p.Glu485Ter Likely pathogenic ★★ same type
EZH1 p.Ala268Gly Uncertain significance ★★ ⚠ same type
EZH1 p.Asp203Asn Uncertain significance ★★ ⚠ same type
EZH1 p.Leu735Phe Uncertain significance ★★ ⚠ same type
EZH1 c.1660+1G>A Likely pathogenic ★ same type
EZH1 c.932-1G>A Likely pathogenic ★ same type
EZH1 p.Gln731Glu Likely pathogenic ★ 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/ezh1-p-pro332arg (accessed [today's date]).

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