Is EP300 p.Ser2126= (c.6378C>T) pathogenic?

EP300 p.Ser2126= (c.6378C>T) is classified Benign in EP300 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-27). Very rare (popmax 0.00659%, sas); Associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency.

What condition is associated with EP300 p.Ser2126= (c.6378C>T)?

EP300 p.Ser2126= (c.6378C>T) is associated with Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (ClinVar).

How common is EP300 p.Ser2126= (c.6378C>T) in the general population?

EP300 p.Ser2126= (c.6378C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

EP300 p.Ser2126=

c.6378C>T · rs368321182 · VCV2169376

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

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 -0.23	GERP -3.9
Overall
CADD	4.261	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,084 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00062% 10/1,614,104 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
East Asian	0.00446%	22,434
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	8.47e-05%	1,179,981

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.Ser2126=
Coding: c.6378C>T
MANE Select: NM_001429
dbSNP: rs368321182
Type: single nucleotide variant
Location: chr22:41178089 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 2126: 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.Ser2126Cys Uncertain significance ★ same residue
EP300 p.Ser2126Phe 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

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-ser2126 (accessed [today's date]).

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