Is EP300 p.Ser1396Pro (c.4186T>C) pathogenic?

EP300 p.Ser1396Pro (c.4186T>C) is classified Conflicting classifications of pathogenicity in EP300 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-02). AlphaMissense: likely pathogenic (0.9972); Absent from gnomAD v4.1; Associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency.

What condition is associated with EP300 p.Ser1396Pro (c.4186T>C)?

EP300 p.Ser1396Pro (c.4186T>C) is associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (ClinVar).

How common is EP300 p.Ser1396Pro (c.4186T>C) in the general population?

EP300 p.Ser1396Pro (c.4186T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EP300 p.Ser1396Pro (c.4186T>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

EP300 p.Ser1396Pro

c.4186T>C · rs2517822537 · VCV2023641

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic · top 9% in EP300
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -8.39	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 8,625 bp · p 4.9e-35 · regional, not allelic
Overall
CADD	25.7	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

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.Ser1396Pro
Coding: c.4186T>C
MANE Select: NM_001429
dbSNP: rs2517822537
Type: single nucleotide variant
Location: chr22:41169516 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 1396: a β-strand; the cbp/p300-type hat domain

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

Disease context

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EP300 p.Ser1396= 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-ser1396pro (accessed [today's date]).

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