Is EPAS1 p.Pro666= (c.1998G>A) pathogenic?

EPAS1 p.Pro666= (c.1998G>A) is classified Likely benign in EPAS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-18). Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Pro666= (c.1998G>A)?

EPAS1 p.Pro666= (c.1998G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Pro666= (c.1998G>A) in the general population?

EPAS1 p.Pro666= (c.1998G>A) is very rare (popmax 0.005%, amr) (gnomAD).

EPAS1 p.Pro666=

c.1998G>A · rs368445079 · VCV1784097

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -2.6
Overall
CADD	0.012	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,000 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00266% 43/1,613,828 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,000
European (non-Finnish)	0.00305%	32,779
East Asian	0.00223%	44,896
South Asian	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro666=
Coding: c.1998G>A
MANE Select: NM_001430
dbSNP: rs368445079
Type: single nucleotide variant
Location: chr2:46380670 (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.Pro666Gln Uncertain significance ★ ⚠ same residue
EPAS1 p.Pro666Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EPAS1 p.Pro666Ser 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

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-pro666 (accessed [today's date]).

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