Is EP300 p.Cys351Trp (c.1053C>G) pathogenic?

EP300 p.Cys351Trp (c.1053C>G) is classified Uncertain significance in EP300 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is EP300 p.Cys351Trp (c.1053C>G) in the general population?

EP300 p.Cys351Trp (c.1053C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EP300 p.Cys351Trp (c.1053C>G)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

EP300 p.Cys351Trp

c.1053C>G · rs1388226313 · VCV1702625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 4% in EP300
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -16.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 2,421 bp · p 5.1e-09 · regional, not allelic
Overall
CADD	24.7	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: EP300
Protein: p.Cys351Trp
Coding: c.1053C>G
MANE Select: NM_001429
dbSNP: rs1388226313
Type: single nucleotide variant
Location: chr22:41127633 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 351: an α-helix; a binding site

Full EP300 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EP300 c.1282+1G>A Pathogenic/Likely pathogenic ★★ same type
EP300 c.3671+1G>A Pathogenic/Likely pathogenic ★★ same type
EP300 c.3729-2A>G Pathogenic/Likely pathogenic ★★ same type
EP300 c.3857A>G Pathogenic/Likely pathogenic ★★ ⚠ same type
EP300 p.Arg1055Ter Pathogenic ★★ same type
EP300 p.Arg1312Ter Pathogenic ★★ same type
EP300 p.Arg1356Ter Pathogenic ★★ same type
EP300 p.Arg1462Ter 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/ep300-p-cys351trp (accessed [today's date]).

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