Is EPAS1 p.Leu43Val (c.127C>G) pathogenic?

EPAS1 p.Leu43Val (c.127C>G) is classified Uncertain significance in EPAS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.2348); Very rare (popmax 0.00356%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Leu43Val (c.127C>G)?

EPAS1 p.Leu43Val (c.127C>G) is associated with Inborn genetic diseases, erythrocytosis, familial, 4 (ClinVar).

How common is EPAS1 p.Leu43Val (c.127C>G) in the general population?

EPAS1 p.Leu43Val (c.127C>G) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about EPAS1 p.Leu43Val (c.127C>G)?

AlphaMissense predicts likely benign (score 0.2348) — an in-silico prediction, not a clinical call.

EPAS1 p.Leu43Val

c.127C>G · rs752221582 · VCV1767494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2348 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2348	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -10.73	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.6, phastCons 0.79
Regional constraint	o/e 0.84	unconstrained · MANE · 78 kb · p 0.0012 · regional, not allelic
Overall
CADD	21.2	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 0.00356% European (non-Finnish) · 42/1,180,032 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00279% 45/1,614,100 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,096
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Admixed American	0.00167%	60,014

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.Leu43Val
Coding: c.127C>G
MANE Select: NM_001430
dbSNP: rs752221582
Type: single nucleotide variant
Location: chr2:46346973 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 43: the bhlh domain; the 'dna-binding' region

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.Leu43= 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
EPAS1 p.Ala758Thr 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-leu43val (accessed [today's date]).

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