Is EPAS1 p.Ser474= (c.1422C>T) pathogenic?

EPAS1 p.Ser474= (c.1422C>T) is classified Likely benign in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). Ultra-rare (popmax 0.0112%, eas); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Ser474= (c.1422C>T)?

EPAS1 p.Ser474= (c.1422C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Ser474= (c.1422C>T) in the general population?

EPAS1 p.Ser474= (c.1422C>T) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

EPAS1 p.Ser474=

c.1422C>T · rs1293640518 · VCV1772284

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.28	GERP -0.53, phastCons 0.38
Overall
CADD	12.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,618 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00277%

Overall 0.000312% 5/1,605,002 alleles · ultra-rare exomes 5/1,452,714 · genomes 0/152,288 · joint denominator

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.Ser474=
Coding: c.1422C>T
MANE Select: NM_001430
dbSNP: rs1293640518
Type: single nucleotide variant
Location: chr2:46378066 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 474: the 'disordered' 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

Similar variants

EPAS1 p.Ser474Asn 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
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-ser474 (accessed [today's date]).

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