Is EED p.Arg133Trp (c.397C>T) pathogenic?

EED p.Arg133Trp (c.397C>T) is classified Uncertain significance in EED (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-08). AlphaMissense: likely pathogenic (0.6193); Very rare (popmax 8.5e-05%, nfe); Associated with Cohen-Gibson syndrome.

What condition is associated with EED p.Arg133Trp (c.397C>T)?

EED p.Arg133Trp (c.397C>T) is associated with Cohen-Gibson syndrome (ClinVar).

How common is EED p.Arg133Trp (c.397C>T) in the general population?

EED p.Arg133Trp (c.397C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about EED p.Arg133Trp (c.397C>T)?

AlphaMissense predicts likely pathogenic (score 0.6193) — an in-silico prediction, not a clinical call.

EED p.Arg133Trp

c.397C>T · rs745786094 · VCV1487012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cohen-Gibson syndrome

Computational evidence

Protein change
AlphaMissense	0.6193	likely pathogenic
REVEL	0.363	indeterminate
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 28 kb · p 8.5e-32 · regional, not allelic
Overall
CADD	32.0	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 8.5e-05% European (non-Finnish) · 1/1,176,746 alleles

Overall 6.86e-05% 1/1,457,244 alleles · very rare

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: EED
Protein: p.Arg133Trp
Coding: c.397C>T
MANE Select: NM_003797
dbSNP: rs745786094
Type: single nucleotide variant
Location: chr11:86255258 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.21 · 81 PDB
Residue 133: the 'interaction with ezh2' region; a β-strand

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

Disease context

Cohen-Gibson syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EED p.Arg133= Likely benign ★ same residue
EED p.Asn194Ser Pathogenic/Likely pathogenic ★★ same condition
EED p.Asp237Gly Likely pathogenic ★★ same condition
EED p.Ala17Val Uncertain significance ★★ ⚠ same condition
EED p.Arg4Met Uncertain significance ★★ ⚠ same condition
EED p.Lys83Ile Uncertain significance ★★ ⚠ same condition
EED c.267+20C>G Benign/Likely benign ★★ same condition
EED c.361-19G>A Likely benign ★★ 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/eed-p-arg133trp (accessed [today's date]).

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