Is EPAS1 p.Ile99Phe (c.295A>T) pathogenic?

EPAS1 p.Ile99Phe (c.295A>T) is classified Uncertain significance in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: ambiguous (0.4762); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Ile99Phe (c.295A>T)?

EPAS1 p.Ile99Phe (c.295A>T) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Ile99Phe (c.295A>T) in the general population?

EPAS1 p.Ile99Phe (c.295A>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about EPAS1 p.Ile99Phe (c.295A>T)?

AlphaMissense predicts ambiguous (score 0.4762) — an in-silico prediction, not a clinical call.

EPAS1 p.Ile99Phe

c.295A>T · VCV3508976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4762	ambiguous
REVEL	0.164	moderately benign-leaning
SaProt	LLR -8.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP -2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 78 kb · p 0.0012 · regional, not allelic
Overall
CADD	23.5	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 0.00134% African / African-American · 1/74,582 alleles

Overall 0.000661% 1/151,262 alleles · very rare

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.Ile99Phe
Coding: c.295A>T
MANE Select: NM_001430
Type: single nucleotide variant
Location: chr2:46356228 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 99: the pas 1 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.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
EPAS1 p.Arg181Cys 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-ile99phe (accessed [today's date]).

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