Is EZH1 p.Ser9Phe (c.26C>T) pathogenic?

EZH1 p.Ser9Phe (c.26C>T) is classified Uncertain significance in EZH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: ambiguous (0.4731); Very rare (popmax 0.00167%, amr).

How common is EZH1 p.Ser9Phe (c.26C>T) in the general population?

EZH1 p.Ser9Phe (c.26C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EZH1 p.Ser9Phe (c.26C>T)?

AlphaMissense predicts ambiguous (score 0.4731) — an in-silico prediction, not a clinical call.

EZH1 p.Ser9Phe

c.26C>T · rs867508196 · VCV2261664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4731	ambiguous
REVEL	0.655	pathogenic-leaning
SaProt	LLR -8.38	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
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 0.81	unconstrained · MANE · 4,592 bp · p 0.029 · regional, not allelic
Overall
CADD	26.8	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 0.00167% Admixed American · 1/59,890 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,074 alleles · very rare exomes 2/1,461,262 · genomes 1/151,812 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,890
European (non-Finnish)	0.00017%	589,842

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.Ser9Phe
Coding: c.26C>T
MANE Select: NM_001991
dbSNP: rs867508196
Type: single nucleotide variant
Location: chr17:42728916 (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-ser9phe (accessed [today's date]).

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