# NM_001429.4(EP300):c.104_107del (p.Ser35fs)

https://sugi.bio/variant/ep300-p-ser35fs

## Summary

**EP300 p.Ser35fs (c.104_107del)** is classified **Pathogenic/Likely pathogenic** in EP300 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-07-15). No gnomAD frequency available for this variant; Associated with EP300-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs886037664 · 9 submitters · 5 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EP300 gene that is considered likely disease-causing, submitted by 9 submitters, and is linked to EP300-related disorder.

*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:** [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.Ser35fs |
| Coding change (HGVS c.) | c.104_107del |
| MANE Select transcript | [NM_001429](https://www.ncbi.nlm.nih.gov/nuccore/NM_001429) |
| dbSNP | [rs886037664](https://www.ncbi.nlm.nih.gov/snp/rs886037664/) |
| Variant type | Microsatellite |
| Location | chr22:41117194-41117197 (GRCh38) |
| ClinVar | [VCV137620](https://www.ncbi.nlm.nih.gov/clinvar/variation/137620/) |

**All HGVS expressions:** `LRG_1422:g.29585CT[1]`, `LRG_1422t1:c.104_107del`, `NC_000022.10:g.41513198CT[1]`, `NC_000022.11:g.41117194CT[1]`, `NG_009817.1:g.29585CT[1]`, `NM_001362843.2:c.104_107del`, `NM_001429.3:c.104_107delCTCT`, `NM_001429.4:c.104_107del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.864, GERP 2.44, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.164, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 31**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **35** lies in the 'interaction with alx1' region; the 'interaction with rora' region.

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.Ser35fs falls in the interaction with alx1 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-15.

**Submitter consensus:** conflicting (8 Pathogenic, 1 Likely pathogenic).

**Submission history:** 9 submissions (2014–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-15 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-12-31 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2014-01-01 |
| Wessex Regional Genetics Laboratory, Salisbury District Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2019-11-05 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2020-05-20 |
| Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-09-06 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-15 |

## Associated conditions {#conditions}

[EP300-related disorder](https://sugi.bio/atlas/disease/ep300-related-disorder/), [colorectal cancer](https://sugi.bio/atlas/disease/colorectal-cancer/), [Rubinstein-Taybi syndrome due to CREBBP mutations](https://sugi.bio/atlas/disease/rubinstein-taybi-syndrome-due-to-crebbp-mutations/), [Rubinstein-Taybi syndrome due to EP300 haploinsufficiency](https://sugi.bio/atlas/disease/rubinstein-taybi-syndrome-due-to-ep300-haploinsufficiency/), [Menke-Hennekam syndrome 2](https://sugi.bio/atlas/disease/menke-hennekam-syndrome-2/).

**Reported phenotype names (ClinVar):** EP300-related disorder, Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, not provided, Neurodevelopmental delay, Colorectal cancer, Menke-Hennekam syndrome 2, Rubinstein-Taybi syndrome due to CREBBP mutations, EP300-related disorders, EP300-related condition, EP300-Related Rubinstein-Taybi Syndrome.

## Similar variants {#similar}

Related EP300 variant pages (same residue, condition, or type): [EP300 p.Ser35Ala](/variant/ep300-p-ser35ala), [EP300 p.Ser35Cys](/variant/ep300-p-ser35cys), [EP300 c.1760+6_1760+9del](/variant/ep300-c-1760-plus-6-1760-plus-9del), [EP300 p.Thr858_Ile859insThr](/variant/ep300-p-thr858-ile859insthr), [EP300 c.4780-11_4780-8del](/variant/ep300-c-4780-minus-11-4780-minus-8del), [EP300 p.Ala394fs](/variant/ep300-p-ala394fs), [EP300 p.Cys1790del](/variant/ep300-p-cys1790del), [EP300 p.Gln2408fs](/variant/ep300-p-gln2408fs).

### 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 137620). 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.*