Is EP300 p.Pro2323Ser (c.6967C>T) pathogenic?

EP300 p.Pro2323Ser (c.6967C>T) is classified Conflicting classifications of pathogenicity in EP300 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-05-19). AlphaMissense: ambiguous (0.4506); Very rare (popmax 0.00373%, nfe); Associated with EP300-related disorder.

What condition is associated with EP300 p.Pro2323Ser (c.6967C>T)?

EP300 p.Pro2323Ser (c.6967C>T) is associated with EP300-related disorder, Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (ClinVar).

How common is EP300 p.Pro2323Ser (c.6967C>T) in the general population?

EP300 p.Pro2323Ser (c.6967C>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about EP300 p.Pro2323Ser (c.6967C>T)?

AlphaMissense predicts ambiguous (score 0.4506) — an in-silico prediction, not a clinical call.

EP300 p.Pro2323Ser

c.6967C>T · rs201369756 · VCV1397869

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4506 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

EP300-related disorder

Computational evidence

Protein change
AlphaMissense	0.4506	ambiguous
REVEL	0.271	benign-leaning
SaProt	LLR -7.23	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 1.2, phastCons 0.97
Regional constraint	o/e 1.26	unconstrained · MANE · 1,737 bp · p 6.7e-13 · regional, not allelic
Overall
CADD	22.7	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 0.00373% European (non-Finnish) · 44/1,180,046 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00285% 46/1,614,082 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,819
African / African-American	0.00267%	37,461

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.Pro2323Ser
Coding: c.6967C>T
MANE Select: NM_001429
dbSNP: rs201369756
Type: single nucleotide variant
Location: chr22:41178678 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 2323: the 'disordered' region

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

Disease context

EP300-related disorder

Also linked: Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Similar variants

EP300 p.Pro2323= Benign/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
EP300 p.Arg1356Ter 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-pro2323ser (accessed [today's date]).

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