Is EPAS1 p.Pro781Leu (c.2342C>T) pathogenic?

EPAS1 p.Pro781Leu (c.2342C>T) is classified Conflicting classifications of pathogenicity in EPAS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-15). AlphaMissense: likely benign (0.0806); Ultra-rare (popmax 0.0766%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Pro781Leu (c.2342C>T)?

EPAS1 p.Pro781Leu (c.2342C>T) is associated with Inborn genetic diseases, erythrocytosis, familial, 4 (ClinVar).

How common is EPAS1 p.Pro781Leu (c.2342C>T) in the general population?

EPAS1 p.Pro781Leu (c.2342C>T) is ultra-rare (popmax 0.0766%, amr) (gnomAD).

What do computational predictors say about EPAS1 p.Pro781Leu (c.2342C>T)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

EPAS1 p.Pro781Leu

c.2342C>T · rs199997193 · VCV1789887

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0766%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.75	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 3.1	GERP 0.6, phastCons 0.18
Regional constraint	o/e 1.18	unconstrained · MANE · 4,363 bp · p 0.00029 · regional, not allelic
Overall
CADD	17.84	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 0.0766% Admixed American · 46/60,036 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.00613% 99/1,614,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0766%	1,305
African / African-American	0.0187%	5,360
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,627
South Asian	0.00439%	22,771
European (non-Finnish)	0.00254%	39,334

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.Pro781Leu
Coding: c.2342C>T
MANE Select: NM_001430
dbSNP: rs199997193
Type: single nucleotide variant
Location: chr2:46382479 (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.Pro781= 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-pro781leu (accessed [today's date]).

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