# NM_001430.5(EPAS1):c.855C>T (p.Asp285=)

https://sugi.bio/variant/epas1-p-asp285

## Summary

**EPAS1 p.Asp285= (c.855C>T)** is classified **Likely benign** in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-11). Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · rsID rs778558626 · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the EPAS1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [EPAS1](https://sugi.bio/atlas/gene/EPAS1/) |
| Protein change (HGVS p.) | p.Asp285= |
| Coding change (HGVS c.) | c.855C>T |
| MANE Select transcript | [NM_001430](https://www.ncbi.nlm.nih.gov/nuccore/NM_001430) |
| dbSNP | [rs778558626](https://www.ncbi.nlm.nih.gov/snp/rs778558626/) |
| Variant type | single nucleotide variant |
| Location | chr2:46369902-46369902 (GRCh38) |
| ClinVar | [VCV1763852](https://www.ncbi.nlm.nih.gov/clinvar/variation/1763852/) |

**All HGVS expressions:** `NC_000002.11:g.46597041C>T`, `NC_000002.12:g.46369902C>T`, `NG_016000.1:g.77501C>T`, `NM_001430.5:c.855C>T`

## 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 1.448, GERP -0.514, phastCons 1 — weakly conserved position
- CADD: **PHRED 10.02**. 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: **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 (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,270 in the highest group · 1/1,460,092 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**EPAS1** population constraint: LOEUF 0.366, pLI 1, missense-Z 0.22063. *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 **285** lies in the pas 2 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 59.41, 30% of residues very-high.

**43 experimental structure(s)** (PDB): [1P97](https://www.rcsb.org/structure/1P97), [2A24](https://www.rcsb.org/structure/2A24), [3F1N](https://www.rcsb.org/structure/3F1N), [3F1O](https://www.rcsb.org/structure/3F1O), [3F1P](https://www.rcsb.org/structure/3F1P), [3H7W](https://www.rcsb.org/structure/3H7W) — incl. mutant structure 8RUT.

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

*Describes the biological roles of EPAS1 (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:** EPAS1's established molecular role includes transcription coactivator binding. p.Asp285= falls in the pas 2 domain.


### Pathways affected {#pathways}

EPAS1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cellular response to hypoxia](https://reactome.org/content/detail/R-HSA-1234174) | other |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | other |
| [Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha](https://reactome.org/content/detail/R-HSA-1234176) | other |
| [PTK6 Expression](https://reactome.org/content/detail/R-HSA-8849473) | other |
| [Pexophagy](https://reactome.org/content/detail/R-HSA-9664873) | other |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | other |
| [Regulation of gene expression by Hypoxia-inducible Factor](https://reactome.org/content/detail/R-HSA-1234158) | other |
| [Transcriptional regulation of pluripotent stem cells](https://reactome.org/content/detail/R-HSA-452723) | other |

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

**Molecular function:** transcription coactivator binding, protein heterodimerization activity, RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** response to hypoxia, positive regulation of transcription by RNA polymerase II, cellular response to hypoxia, regulation of protein neddylation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related EPAS1 variant pages (same residue, condition, or type): [EPAS1 p.Asp285Asn](/variant/epas1-p-asp285asn), [EPAS1 p.Asp285Tyr](/variant/epas1-p-asp285tyr), [EPAS1 p.Ala439Gly](/variant/epas1-p-ala439gly), [EPAS1 p.Ala463Thr](/variant/epas1-p-ala463thr), [EPAS1 p.Ala698Pro](/variant/epas1-p-ala698pro), [EPAS1 p.Ala758Thr](/variant/epas1-p-ala758thr), [EPAS1 p.Ala81Thr](/variant/epas1-p-ala81thr), [EPAS1 p.Ala83Asp](/variant/epas1-p-ala83asp).

### 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 1763852). 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.*