# NM_015409.5(EP400):c.1323T>C (p.Val441=)

https://sugi.bio/variant/ep400-p-val441

## Summary

**EP400 p.Val441= (c.1323T>C)** is classified **Likely benign** in EP400 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-05-18). No allele count reported in gnomAD v4.1 (AN 1,611,636); Associated with EP400-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs1329649668 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,611,636)

## For patients & families {#patients}

This is a change in the EP400 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to EP400-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 | [EP400](https://sugi.bio/atlas/gene/EP400/) |
| Protein change (HGVS p.) | p.Val441= |
| Coding change (HGVS c.) | c.1323T>C |
| MANE Select transcript | [NM_015409](https://www.ncbi.nlm.nih.gov/nuccore/NM_015409) |
| dbSNP | [rs1329649668](https://www.ncbi.nlm.nih.gov/snp/rs1329649668/) |
| Variant type | single nucleotide variant |
| Location | chr12:131961942-131961942 (GRCh38) |
| ClinVar | [VCV3054659](https://www.ncbi.nlm.nih.gov/clinvar/variation/3054659/) |

**All HGVS expressions:** `NC_000012.11:g.132446487T>C`, `NC_000012.12:g.131961942T>C`, `NM_015409.5:c.1323T>C`

## Computational & population evidence {#evidence}

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

- **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 -0.617, phastCons 0.043 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.713**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.57 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,611,636)** — 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}

**EP400** population constraint: LOEUF 0.365, pLI 1, missense-Z 4.1628. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


**13 experimental structure(s)** (PDB): [8QR1](https://www.rcsb.org/structure/8QR1), [8QRI](https://www.rcsb.org/structure/8QRI), [8XVG](https://www.rcsb.org/structure/8XVG), [8XVT](https://www.rcsb.org/structure/8XVT), [8XVV](https://www.rcsb.org/structure/8XVV), [9C47](https://www.rcsb.org/structure/9C47).

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

*Describes the biological roles of EP400 (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.*


### Pathways affected {#pathways}

EP400 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Formation of Senescence-Associated Heterochromatin Foci (SAHF)](https://reactome.org/content/detail/R-HSA-2559584) | curated |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |

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

**Biological process:** nervous system development, regulation of cell cycle, positive regulation of double-strand break repair via homologous recombination.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2021-05-18.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-05-18 |

## Associated conditions {#conditions}

[EP400-related disorder](https://sugi.bio/atlas/disease/ep400-related-disorder/).

**Reported phenotype names (ClinVar):** EP400-related disorder, EP400-related condition.

## Similar variants {#similar}

Related EP400 variant pages (same residue, condition, or type): [EP400 p.Gly2702Glu](/variant/ep400-p-gly2702glu), [EP400 p.Lys1297Arg](/variant/ep400-p-lys1297arg), [EP400 p.Ser45Pro](/variant/ep400-p-ser45pro), [EP400 p.Ser573Phe](/variant/ep400-p-ser573phe), [EP400 c.2680-3C>A](/variant/ep400-c-2680-minus-3c-a), [EP400 c.4110+2T>A](/variant/ep400-c-4110-plus-2t-a), [EP400 c.5584+1G>A](/variant/ep400-c-5584-plus-1g-a), [EP400 p.Arg1295Ter](/variant/ep400-p-arg1295ter).

### 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 3054659). 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.*