Is EPAS1 p.Pro534Leu (c.1601C>T) pathogenic?

EPAS1 p.Pro534Leu (c.1601C>T) is classified Likely pathogenic in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely pathogenic (0.9437); Absent from gnomAD v4.1; Associated with erythrocytosis, familial, 4.

What condition is associated with EPAS1 p.Pro534Leu (c.1601C>T)?

EPAS1 p.Pro534Leu (c.1601C>T) is associated with erythrocytosis, familial, 4 (ClinVar).

How common is EPAS1 p.Pro534Leu (c.1601C>T) in the general population?

EPAS1 p.Pro534Leu (c.1601C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPAS1 p.Pro534Leu (c.1601C>T)?

AlphaMissense predicts likely pathogenic (score 0.9437) — an in-silico prediction, not a clinical call.

EPAS1 p.Pro534Leu

c.1601C>T · rs2546476675 · VCV2920985

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9437 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

erythrocytosis, familial, 4

Computational evidence

Protein change
AlphaMissense	0.9437	likely pathogenic ✓ concordant with ClinVar
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -5.17	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.06	constrained · MANE · 38 bp · p 5.8e-05 · regional, not allelic
Overall
CADD	26.4	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.Pro534Leu
Coding: c.1601C>T
MANE Select: NM_001430
dbSNP: rs2546476675
Type: single nucleotide variant
Location: chr2:46380273 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 534: a UniProt-annotated variant site (in ecyt4; impairs interaction with egln1 and vhl); the 'ntad' region

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

Disease context

erythrocytosis, familial, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPAS1 p.Pro534Arg Likely pathogenic ★ ⚠ same residue
EPAS1 p.Pro534= Likely benign ★ same residue
EPAS1 p.Gly537Arg Pathogenic ★★ same condition
EPAS1 p.Met535Thr Pathogenic ★★ ⚠ same condition
EPAS1 c.-231C>G Uncertain significance ★★ same condition
EPAS1 p.Ala81Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Arg825Gln Uncertain significance ★★ ⚠ same condition
EPAS1 p.Cys74Gly 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-pro534leu (accessed [today's date]).

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