# NM_015409.5(EP400):c.1779G>A (p.Pro593=)

https://sugi.bio/variant/ep400-p-pro593

## Summary

**EP400 p.Pro593= (c.1779G>A)** is classified **Benign** in EP400 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-09-19). Low-frequency (popmax 3.03%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs147639500 · 3 submitters · low-frequency (popmax 3.03%, afr)

## For patients & families {#patients}

This is a change in the EP400 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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.Pro593= |
| Coding change (HGVS c.) | c.1779G>A |
| MANE Select transcript | [NM_015409](https://www.ncbi.nlm.nih.gov/nuccore/NM_015409) |
| dbSNP | [rs147639500](https://www.ncbi.nlm.nih.gov/snp/rs147639500/) |
| Variant type | single nucleotide variant |
| Location | chr12:131982328-131982328 (GRCh38) |
| ClinVar | [VCV776780](https://www.ncbi.nlm.nih.gov/clinvar/variation/776780/) |

**All HGVS expressions:** `NC_000012.11:g.132466873G>A`, `NC_000012.12:g.131982328G>A`, `NM_015409.5:c.1779G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -20, GERP -3.11 — fast-evolving / accelerated position
- CADD: **PHRED 0.024**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **3.03%** (afr) · FAF95 2.93% · FAF99 2.88% · 2,273/75,018 in the highest group · 2,618/1,614,096 alleles overall — low-frequency (popmax 3.03%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.03% | 33 |
| Remaining individuals (not grpmax-eligible) | 0.213% | 470 |
| Admixed American | 0.148% | 674 |
| Middle Eastern | 0.132% | 758 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0473% | 2,115 |
| South Asian | 0.0143% | 7,007 |
| European (non-Finnish) | 0.00712% | 14,048 |
| East Asian | 0.00669% | 14,951 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,008 |

*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}

Residue **593** lies in the 'disordered' region.

**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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-09-19.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2018–2020); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-09-19 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-02-17 |

**Reported phenotype names (ClinVar):** not provided, EP400-related disorder, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided, EP400-related condition.

## Similar variants {#similar}

Related EP400 variant pages (same residue, condition, or type): [EP400 p.Pro593Ala](/variant/ep400-p-pro593ala), [EP400 p.Pro593Leu](/variant/ep400-p-pro593leu), [EP400 p.Thr664Ala](/variant/ep400-p-thr664ala), [EP400 c.1435+8G>A](/variant/ep400-c-1435-plus-8g-a), [EP400 c.7027-9C>T](/variant/ep400-c-7027-minus-9c-t), [EP400 p.Ala146=](/variant/ep400-p-ala146), [EP400 p.Ala1649Thr](/variant/ep400-p-ala1649thr), [EP400 p.Ala1764=](/variant/ep400-p-ala1764).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 776780). 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.*