Is EZH1 p.Pro559Ser (c.1675C>T) pathogenic?

EZH1 p.Pro559Ser (c.1675C>T) is classified Uncertain significance in EZH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.9922); Absent from gnomAD v4.1.

How common is EZH1 p.Pro559Ser (c.1675C>T) in the general population?

EZH1 p.Pro559Ser (c.1675C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EZH1 p.Pro559Ser (c.1675C>T)?

AlphaMissense predicts likely pathogenic (score 0.9922) — an in-silico prediction, not a clinical call.

EZH1 p.Pro559Ser

c.1675C>T · VCV4686301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9922 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9922	likely pathogenic
REVEL	0.562	indeterminate
SaProt	LLR -10.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 1,949 bp · p 1.4e-11 · regional, not allelic
Overall
CADD	29.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EZH1
Protein: p.Pro559Ser
Coding: c.1675C>T
MANE Select: NM_001991
Type: single nucleotide variant
Location: chr17:42706171 (GRCh38)
Gene constraint: LOEUF 0.439 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.05 · 4 PDB
Residue 559: the cxc domain

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-pro559ser (accessed [today's date]).

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