Is EPAS1 p.Ile61Val (c.181A>G) pathogenic?

EPAS1 p.Ile61Val (c.181A>G) is classified Likely benign in EPAS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.3047); Rare (popmax 0.128%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Ile61Val (c.181A>G)?

EPAS1 p.Ile61Val (c.181A>G) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Ile61Val (c.181A>G) in the general population?

EPAS1 p.Ile61Val (c.181A>G) is rare (popmax 0.128%, amr) (gnomAD).

What do computational predictors say about EPAS1 p.Ile61Val (c.181A>G)?

AlphaMissense predicts likely benign (score 0.3047) — an in-silico prediction, not a clinical call.

EPAS1 p.Ile61Val

c.181A>G · rs757224585 · VCV2456403

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3047 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.128%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3047	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -9.42	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 78 kb · p 0.0012 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 0.128% Admixed American · 77/60,006 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0968%

Overall 0.00514% 83/1,614,070 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.128%	779
Remaining individualsnot grpmax-eligible	0.0064%	15,623
European (non-Finnish)	0.000169%	590,016

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.Ile61Val
Coding: c.181A>G
MANE Select: NM_001430
dbSNP: rs757224585
Type: single nucleotide variant
Location: chr2:46347027 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 61: the bhlh domain

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.Ile61= Likely benign ★ 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-ile61val (accessed [today's date]).

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