Is EP300 p.Val486Met (c.1456G>A) pathogenic?

EP300 p.Val486Met (c.1456G>A) is classified Conflicting classifications of pathogenicity in EP300 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0934); Ultra-rare (popmax 0.0147%, afr); Associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency.

What condition is associated with EP300 p.Val486Met (c.1456G>A)?

EP300 p.Val486Met (c.1456G>A) is associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (ClinVar).

How common is EP300 p.Val486Met (c.1456G>A) in the general population?

EP300 p.Val486Met (c.1456G>A) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about EP300 p.Val486Met (c.1456G>A)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

EP300 p.Val486Met

c.1456G>A · VCV3719700

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2.9, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 7,764 bp · p 0.0081 · regional, not allelic
Overall
CADD	23.9	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

Grpmax group 0.0147% African / African-American · 11/74,858 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.000867% 14/1,613,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,805
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	8.47e-05%	1,180,025

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.Val486Met
Coding: c.1456G>A
MANE Select: NM_001429
Type: single nucleotide variant
Location: chr22:41131561 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 486: the 'disordered' region

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.Val486Leu Uncertain significance ★★ ⚠ same residue
EP300 p.Val486= 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-val486met (accessed [today's date]).

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