Is EP300 p.Ala1548Pro (c.4642G>C) pathogenic?

EP300 p.Ala1548Pro (c.4642G>C) is classified Uncertain significance in EP300 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: likely pathogenic (0.9536); Absent from gnomAD v4.1; Associated with Menke-Hennekam syndrome 2.

What condition is associated with EP300 p.Ala1548Pro (c.4642G>C)?

EP300 p.Ala1548Pro (c.4642G>C) is associated with Menke-Hennekam syndrome 2 (ClinVar).

How common is EP300 p.Ala1548Pro (c.4642G>C) in the general population?

EP300 p.Ala1548Pro (c.4642G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EP300 p.Ala1548Pro (c.4642G>C)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

EP300 p.Ala1548Pro

c.4642G>C · VCV3341316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Menke-Hennekam syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic
REVEL	0.554	indeterminate
SaProt	LLR -6.81	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 8,625 bp · p 4.9e-35 · regional, not allelic
Overall
CADD	25.9	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

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.Ala1548Pro
Coding: c.4642G>C
MANE Select: NM_001429
Type: single nucleotide variant
Location: chr22:41173647 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 1548: the 'disordered' region; the cbp/p300-type hat domain

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

Disease context

Menke-Hennekam syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EP300 c.3729-2A>G Pathogenic/Likely pathogenic ★★ same condition
EP300 p.Arg1821Gln Uncertain significance ★★ ⚠ same condition
EP300 p.Gln2262His Uncertain significance ★★ ⚠ same condition
EP300 p.Met2269Ile Uncertain significance ★★ ⚠ same condition
EP300 c.2053+8G>T Benign ★★ same condition
EP300 c.2380-18T>C Benign/Likely benign ★★ same condition
EP300 c.4452+20C>T Benign ★★ same condition
EP300 c.4453-23T>C 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/ep300-p-ala1548pro (accessed [today's date]).

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