Is EP300 p.Ile997Val (c.2989A>G) pathogenic?

EP300 p.Ile997Val (c.2989A>G) is classified Benign in EP300 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0728); Common (popmax 53.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Menke-Hennekam syndrome 2.

What condition is associated with EP300 p.Ile997Val (c.2989A>G)?

EP300 p.Ile997Val (c.2989A>G) is associated with Menke-Hennekam syndrome 2, Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (ClinVar).

What do computational predictors say about EP300 p.Ile997Val (c.2989A>G)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

EP300 p.Ile997Val

Q: How common is EP300 p.Ile997Val (c.2989A>G) in the general population?

EP300 p.Ile997Val (c.2989A>G) is common (popmax 53.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2989A>G · rs20551 · VCV93736

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 53.7%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Menke-Hennekam syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.33, phastCons 0.13
Regional constraint	o/e 1.10	unconstrained · MANE · 11 kb · p 0.024 · regional, not allelic
Overall
CADD	9.384	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 53.7% Admixed American · 32,206/59,990 alleles

Filtering AF 53.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 53%

Overall 28.3% 456,999/1,613,848 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	53.7%	2
Amishnot grpmax-eligible	42.7%	2
South Asian	37.4%	3
Ashkenazi Jewishnot grpmax-eligible	32.6%	3
Finnishnot grpmax-eligible	31.8%	3
European (non-Finnish)	28.4%	4
Middle Eastern	28.3%	4
Remaining individualsnot grpmax-eligible	28%	4
African / African-American	5.38%	19
East Asian	4.34%	23

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.Ile997Val
Coding: c.2989A>G
MANE Select: NM_001429
dbSNP: rs20551
Type: single nucleotide variant
Location: chr22:41152004 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.88 · 60 PDB
Residue 997: a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

Menke-Hennekam syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Similar variants

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
EP300 p.Arg1462Ter 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-ile997val (accessed [today's date]).

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