Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
low-frequency (popmax 3.47%, afr)
Conditions
1
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 -0.36 | GERP -2.6, phastCons 0.28 |
| Overall | ||
| CADD | 7.867 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
3.47%
African / African-American · 2,605/75,048 alleles
Filtering AF
3.36%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 3.31%
Overall
0.185%
2,994/1,614,190 alleles · low-frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 3.47% | 29 |
| Middle Eastern | 0.33% | 303 |
| Admixed American | 0.265% | 378 |
| Remaining individualsnot grpmax-eligible | 0.24% | 417 |
| South Asian | 0.00659% | 15,180 |
| European (non-Finnish) | 0.00458% | 21,852 |
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.Pro673=
- Coding
- c.2019T>C
- MANE Select
- NM_001429
- dbSNP
- rs2230110
- Type
- single nucleotide variant
- Location
- chr22:41141188 (GRCh38)
- Gene constraint
- LOEUF 0.164 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 54.88 · 60 PDB
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-pro673 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown