Is EPAS1 p.Asp357Glu (c.1071C>A) pathogenic?

EPAS1 p.Asp357Glu (c.1071C>A) is classified Uncertain significance in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-16). AlphaMissense: likely pathogenic (0.6272); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Asp357Glu (c.1071C>A)?

EPAS1 p.Asp357Glu (c.1071C>A) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Asp357Glu (c.1071C>A) in the general population?

EPAS1 p.Asp357Glu (c.1071C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPAS1 p.Asp357Glu (c.1071C>A)?

AlphaMissense predicts likely pathogenic (score 0.6272) — an in-silico prediction, not a clinical call.

EPAS1 p.Asp357Glu

c.1071C>A · rs2546471288 · VCV2450305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6272 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6272	likely pathogenic
REVEL	0.168	moderately benign-leaning
SaProt	LLR -3.96	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.14, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 4,474 bp · p 0.11 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPAS1
Protein: p.Asp357Glu
Coding: c.1071C>A
MANE Select: NM_001430
dbSNP: rs2546471288
Type: single nucleotide variant
Location: chr2:46376575 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB

Full EPAS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPAS1 p.Asp357Asn Uncertain significance ★ ⚠ same residue
EPAS1 p.Ala439Gly Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala463Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala698Pro Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala758Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala81Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala83Asp Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala94Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/epas1-p-asp357glu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown