Is EPAS1 p.Pro670Arg (c.2009C>G) pathogenic?

EPAS1 p.Pro670Arg (c.2009C>G) is classified Uncertain significance in EPAS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-20). AlphaMissense: likely benign (0.0881); Ultra-rare (popmax 0.028%, afr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Pro670Arg (c.2009C>G)?

EPAS1 p.Pro670Arg (c.2009C>G) is associated with Inborn genetic diseases, erythrocytosis, familial, 4 (ClinVar).

How common is EPAS1 p.Pro670Arg (c.2009C>G) in the general population?

EPAS1 p.Pro670Arg (c.2009C>G) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about EPAS1 p.Pro670Arg (c.2009C>G)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

EPAS1 p.Pro670Arg

c.2009C>G · rs139763806 · VCV2441241

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -6.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.19, phastCons 0.34
Regional constraint	o/e 1.18	unconstrained · MANE · 4,363 bp · p 0.00029 · regional, not allelic
Overall
CADD	16.99	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/75,044 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00149% 24/1,613,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,574
Remaining individualsnot grpmax-eligible	0.0032%	31,253
East Asian	0.00223%	44,888

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPAS1
Protein: p.Pro670Arg
Coding: c.2009C>G
MANE Select: NM_001430
dbSNP: rs139763806
Type: single nucleotide variant
Location: chr2:46380681 (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

Also linked: erythrocytosis, familial, 4

Similar variants

EPAS1 p.Pro670Ala Uncertain significance ★ ⚠ same residue
EPAS1 p.Pro670= 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.Ala439Gly Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala463Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala698Pro 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-pro670arg (accessed [today's date]).

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