Is EPAS1 p.Phe374Tyr (c.1121T>A) pathogenic?

EPAS1 p.Phe374Tyr (c.1121T>A) is classified Conflicting classifications of pathogenicity in EPAS1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1596); Rare (popmax 0.625%, nfe); Associated with erythrocytosis, familial, 4.

What condition is associated with EPAS1 p.Phe374Tyr (c.1121T>A)?

EPAS1 p.Phe374Tyr (c.1121T>A) is associated with erythrocytosis, familial, 4 (ClinVar).

How common is EPAS1 p.Phe374Tyr (c.1121T>A) in the general population?

EPAS1 p.Phe374Tyr (c.1121T>A) is rare (popmax 0.625%, nfe) (gnomAD).

What do computational predictors say about EPAS1 p.Phe374Tyr (c.1121T>A)?

AlphaMissense predicts likely benign (score 0.1596) — an in-silico prediction, not a clinical call.

EPAS1 p.Phe374Tyr

c.1121T>A · rs150797491 · VCV336261

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1596 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.625%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

erythrocytosis, familial, 4

Computational evidence

Protein change
AlphaMissense	0.1596	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -6.49	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 4,474 bp · p 0.11 · regional, not allelic
Overall
CADD	23.0	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 0.625% European (non-Finnish) · 7,375/1,180,024 alleles

Filtering AF 0.613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.608%

Overall 0.534% 8,614/1,614,160 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.625%	160
Middle Eastern	0.528%	189
Remaining individualsnot grpmax-eligible	0.453%	221
Admixed American	0.382%	262
South Asian	0.345%	290
Finnishnot grpmax-eligible	0.322%	311
Ashkenazi Jewishnot grpmax-eligible	0.277%	361
African / African-American	0.123%	815
East Asian	0.00223%	44,882

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.Phe374Tyr
Coding: c.1121T>A
MANE Select: NM_001430
dbSNP: rs150797491
Type: single nucleotide variant
Location: chr2:46376625 (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

erythrocytosis, familial, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPAS1 p.Phe374Ser Uncertain significance ★ ⚠ same residue
EPAS1 p.Gly537Arg Pathogenic ★★ same condition
EPAS1 p.Met535Thr Pathogenic ★★ ⚠ same condition
EPAS1 c.-231C>G Uncertain significance ★★ same condition
EPAS1 p.Ala81Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Arg825Gln Uncertain significance ★★ ⚠ same condition
EPAS1 p.Cys74Gly Uncertain significance ★★ ⚠ same condition
EPAS1 p.Gly774Ala 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-phe374tyr (accessed [today's date]).

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