Is EP300 p.Val2124= (c.6372C>T) pathogenic?

EP300 p.Val2124= (c.6372C>T) is classified Benign in EP300 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Common (popmax 5.46%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency.

What condition is associated with EP300 p.Val2124= (c.6372C>T)?

EP300 p.Val2124= (c.6372C>T) is associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (ClinVar).

EP300 p.Val2124=

Q: How common is EP300 p.Val2124= (c.6372C>T) in the general population?

EP300 p.Val2124= (c.6372C>T) is common (popmax 5.46%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6372C>T · rs34985152 · VCV158568

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 5.46%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.38	GERP -1.1, phastCons 0.066
Overall
CADD	3.479	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.46% African / African-American · 4,094/75,014 alleles

Filtering AF 5.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.26%

Overall 0.298% 4,818/1,614,102 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.46%	18
Middle Eastern	0.462%	216
Remaining individualsnot grpmax-eligible	0.413%	242
Admixed American	0.395%	253
European (non-Finnish)	0.0159%	6,277
South Asian	0.0143%	7,005

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.Val2124=
Coding: c.6372C>T
MANE Select: NM_001429
dbSNP: rs34985152
Type: single nucleotide variant
Location: chr22:41178083 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 2124: the 'interaction with htlv-1 tax' region; the 'interaction with ncoa2' region; 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.Val2124Phe Uncertain significance ★ ⚠ 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-val2124 (accessed [today's date]).

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