Is EP300 p.Pro2220Arg (c.6659C>G) pathogenic?

EP300 p.Pro2220Arg (c.6659C>G) is classified Benign/Likely benign in EP300 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-27). AlphaMissense: likely benign (0.325); Ultra-rare (popmax 0.0413%, afr); Associated with Inborn genetic diseases.

What condition is associated with EP300 p.Pro2220Arg (c.6659C>G)?

EP300 p.Pro2220Arg (c.6659C>G) is associated with Inborn genetic diseases, Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (ClinVar).

How common is EP300 p.Pro2220Arg (c.6659C>G) in the general population?

EP300 p.Pro2220Arg (c.6659C>G) is ultra-rare (popmax 0.0413%, afr) (gnomAD).

What do computational predictors say about EP300 p.Pro2220Arg (c.6659C>G)?

AlphaMissense predicts likely benign (score 0.325) — an in-silico prediction, not a clinical call.

EP300 p.Pro2220Arg

c.6659C>G · rs555467754 · VCV2043341

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.325 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0413%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.325	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 1,737 bp · p 6.7e-13 · regional, not allelic
Overall
CADD	21.3	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 0.0413% African / African-American · 31/75,040 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00204% 33/1,614,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0413%	2,421
Remaining individualsnot grpmax-eligible	0.0032%	31,252

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: EP300
Protein: p.Pro2220Arg
Coding: c.6659C>G
MANE Select: NM_001429
dbSNP: rs555467754
Type: single nucleotide variant
Location: chr22:41178370 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 2220: the 'interaction with ncoa2' region; the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Similar variants

EP300 p.Pro2220Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EP300 p.Pro2220= Likely benign ★ same residue
EP300 c.1282+1G>A Pathogenic/Likely pathogenic ★★ same condition
EP300 c.3671+1G>A Pathogenic/Likely pathogenic ★★ same condition
EP300 c.3729-2A>G Pathogenic/Likely pathogenic ★★ same condition
EP300 c.3857A>G Pathogenic/Likely pathogenic ★★ ⚠ same condition
EP300 p.Arg1055Ter Pathogenic ★★ same condition
EP300 p.Arg1312Ter Pathogenic ★★ 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-pro2220arg (accessed [today's date]).

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