Is EP300 p.Arg754Cys (c.2260C>T) pathogenic?

EP300 p.Arg754Cys (c.2260C>T) is classified Uncertain significance in EP300 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: ambiguous (0.4352); Very rare (popmax 0.0022%, sas).

How common is EP300 p.Arg754Cys (c.2260C>T) in the general population?

EP300 p.Arg754Cys (c.2260C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EP300 p.Arg754Cys (c.2260C>T)?

AlphaMissense predicts ambiguous (score 0.4352) — an in-silico prediction, not a clinical call.

EP300 p.Arg754Cys

c.2260C>T · rs2145735782 · VCV1311630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
AlphaMissense	0.4352	ambiguous
REVEL	0.52	indeterminate
SaProt	LLR -10.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 11 kb · p 0.024 · regional, not allelic
Overall
CADD	28.2	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 0.0022% South Asian · 2/91,004 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000616% 9/1,461,734 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,502
Remaining individualsnot grpmax-eligible	0.0016%	62,450
European (non-Finnish)	0.000509%	196,616

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.Arg754Cys
Coding: c.2260C>T
MANE Select: NM_001429
dbSNP: rs2145735782
Type: single nucleotide variant
Location: chr22:41149056 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 754: the 'disordered' region

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

Similar variants

EP300 p.Arg754Leu Uncertain significance ★★ ⚠ same residue
EP300 p.Arg754His Uncertain significance ★ ⚠ same residue
EP300 p.Arg754Pro Uncertain significance ★ ⚠ same residue
EP300 c.1282+1G>A Pathogenic/Likely pathogenic ★★ same type
EP300 c.3671+1G>A Pathogenic/Likely pathogenic ★★ same type
EP300 c.3729-2A>G Pathogenic/Likely pathogenic ★★ same type
EP300 c.3857A>G Pathogenic/Likely pathogenic ★★ ⚠ same type
EP300 p.Arg1055Ter Pathogenic ★★ same type

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-arg754cys (accessed [today's date]).

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