# NM_001429.4(EP300):c.4642G>C (p.Ala1548Pro)

https://sugi.bio/variant/ep300-p-ala1548pro

## Summary

**EP300 p.Ala1548Pro (c.4642G>C)** is classified **Uncertain significance** in EP300 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: likely pathogenic (0.9536); Absent from gnomAD v4.1; Associated with Menke-Hennekam syndrome 2.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EP300 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Menke-Hennekam syndrome 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025243/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EP300](https://sugi.bio/atlas/gene/EP300/) |
| Protein change (HGVS p.) | p.Ala1548Pro |
| Coding change (HGVS c.) | c.4642G>C |
| MANE Select transcript | [NM_001429](https://www.ncbi.nlm.nih.gov/nuccore/NM_001429) |
| Variant type | single nucleotide variant |
| Location | chr22:41173647-41173647 (GRCh38) |
| ClinVar | [VCV3341316](https://www.ncbi.nlm.nih.gov/clinvar/variation/3341316/) |

**All HGVS expressions:** `LRG_1422:g.86038G>C`, `LRG_1422t1:c.4642G>C`, `NC_000022.10:g.41569651G>C`, `NC_000022.11:g.41173647G>C`, `NG_009817.1:g.86038G>C`, `NM_001362843.2:c.4564G>C`, `NM_001429.4:c.4642G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9536)
- REVEL 0.554 (indeterminate)
- SaProt LLR -6.814 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 11.722, GERP 2.5, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.51** across the covering region of the MANE Select transcript (41,168,504–41,177,129), spanning 8,625 bp. Chi-square p 4.9e-35. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**EP300** population constraint: LOEUF 0.164, pLI 1, missense-Z 2.6711; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Rubinstein-Taybi syndrome due to EP300 haploinsufficiency** — Definitive (AD)

## Protein context {#protein}

Residue **1548** lies in the 'disordered' region; the cbp/p300-type hat domain.

AlphaFold model confidence (whole protein): pLDDT 54.88, 22% of residues very-high.

**60 experimental structure(s)** (PDB): [1L3E](https://www.rcsb.org/structure/1L3E), [1P4Q](https://www.rcsb.org/structure/1P4Q), [2K8F](https://www.rcsb.org/structure/2K8F), [2MH0](https://www.rcsb.org/structure/2MH0), [2MZD](https://www.rcsb.org/structure/2MZD), [3BIY](https://www.rcsb.org/structure/3BIY) — incl. mutant structure 9JEJ.

## What this gene does {#gene-function}

*Describes the biological roles of EP300 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** EP300's established molecular role includes transcription coregulator binding. p.Ala1548Pro falls in the disordered region. In Reactome, EP300 is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**, **Constitutive Signaling by NOTCH1 PEST Domain Mutants**.

**Disease mechanism (Reactome):** EP300 loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606), [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109).

### Pathways affected {#pathways}

EP300 participates in **62 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | curated |
| ⚕ [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109) | curated |
| ⚕ [SARS-CoV-1 targets host intracellular signalling and regulatory pathways](https://reactome.org/content/detail/R-HSA-9735871) | curated |
| [Activation of the TFAP2 (AP-2) family of transcription factors](https://reactome.org/content/detail/R-HSA-8866907) | curated |
| [Attenuation phase](https://reactome.org/content/detail/R-HSA-3371568) | curated |
| [B-WICH complex positively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-5250924) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | curated |
| [LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production](https://reactome.org/content/detail/R-HSA-3134973) | curated |
| [Metalloprotease DUBs](https://reactome.org/content/detail/R-HSA-5689901) | curated |
| [NFE2L2 regulates pentose phosphate pathway genes](https://reactome.org/content/detail/R-HSA-9818028) | curated |
| [NFE2L2 regulating ER-stress associated genes](https://reactome.org/content/detail/R-HSA-9818035) | curated |
| [NFE2L2 regulating MDR associated enzymes](https://reactome.org/content/detail/R-HSA-9818032) | curated |
| [NFE2L2 regulating inflammation associated genes](https://reactome.org/content/detail/R-HSA-9818026) | curated |
| [NFE2L2 regulating tumorigenic genes](https://reactome.org/content/detail/R-HSA-9818030) | curated |
| [NOTCH4 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013695) | curated |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | curated |
| [Nuclear events mediated by NFE2L2](https://reactome.org/content/detail/R-HSA-9759194) | curated |
| [PI5P Regulates TP53 Acetylation](https://reactome.org/content/detail/R-HSA-6811555) | curated |
| [Polo-like kinase mediated events](https://reactome.org/content/detail/R-HSA-156711) | curated |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [RUNX3 regulates p14-ARF](https://reactome.org/content/detail/R-HSA-8951936) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Regulation of TP53 Activity through Acetylation](https://reactome.org/content/detail/R-HSA-6804758) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Regulation of gene expression by Hypoxia-inducible Factor](https://reactome.org/content/detail/R-HSA-1234158) | curated |
| [SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription](https://reactome.org/content/detail/R-HSA-2173796) | curated |
| [STAT3 nuclear events downstream of ALK signaling](https://reactome.org/content/detail/R-HSA-9701898) | curated |
| [SUMOylation of transcription cofactors](https://reactome.org/content/detail/R-HSA-3899300) | curated |
| [TGFBR3 expression](https://reactome.org/content/detail/R-HSA-9839394) | curated |
| [TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804114) | curated |
| [TRAF3-dependent IRF activation pathway](https://reactome.org/content/detail/R-HSA-918233) | curated |
| [TRAF6 mediated IRF7 activation](https://reactome.org/content/detail/R-HSA-933541) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | electronic |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |
| [FOXO-mediated transcription of cell death genes](https://reactome.org/content/detail/R-HSA-9614657) | electronic |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | electronic |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | electronic |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |
| [NFE2L2 regulating anti-oxidant/detoxification enzymes](https://reactome.org/content/detail/R-HSA-9818027) | electronic |
| [NGF-stimulated transcription](https://reactome.org/content/detail/R-HSA-9031628) | electronic |
| [NOTCH1 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-2122947) | electronic |
| [NOTCH2 intracellular domain regulates transcription](https://reactome.org/content/detail/R-HSA-2197563) | electronic |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | electronic |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | electronic |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | electronic |
| [RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression](https://reactome.org/content/detail/R-HSA-9933387) | electronic |
| [RUNX3 regulates NOTCH signaling](https://reactome.org/content/detail/R-HSA-8941856) | electronic |
| [Regulation of FOXO transcriptional activity by acetylation](https://reactome.org/content/detail/R-HSA-9617629) | electronic |
| [Regulation of NFE2L2 gene expression](https://reactome.org/content/detail/R-HSA-9818749) | electronic |
| [Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells](https://reactome.org/content/detail/R-HSA-210744) | electronic |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |
| [Zygotic genome activation (ZGA)](https://reactome.org/content/detail/R-HSA-9819196) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription coregulator binding, transcription coactivator binding, DNA binding, chromatin binding, damaged DNA binding, transcription coactivator activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, response to hypoxia, regulation of glycolytic process, protein acetylation, internal protein amino acid acetylation, apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-20 |

## Associated conditions {#conditions}

[Menke-Hennekam syndrome 2](https://sugi.bio/atlas/disease/menke-hennekam-syndrome-2/).

**Reported phenotype names (ClinVar):** Menke-Hennekam syndrome 2.

## Similar variants {#similar}

Related EP300 variant pages (same residue, condition, or type): [EP300 c.3729-2A>G](/variant/ep300-c-3729-minus-2a-g), [EP300 p.Arg1821Gln](/variant/ep300-p-arg1821gln), [EP300 p.Gln2262His](/variant/ep300-p-gln2262his), [EP300 p.Met2269Ile](/variant/ep300-p-met2269ile), [EP300 c.2053+8G>T](/variant/ep300-c-2053-plus-8g-t), [EP300 c.2380-18T>C](/variant/ep300-c-2380-minus-18t-c), [EP300 c.4452+20C>T](/variant/ep300-c-4452-plus-20c-t), [EP300 c.4453-23T>C](/variant/ep300-c-4453-minus-23t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3341316). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*