Is EPAS1 p.Ile115= (c.345C>T) pathogenic?

EPAS1 p.Ile115= (c.345C>T) is classified Benign/Likely benign in EPAS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-26). Ultra-rare (popmax 0.0691%, eas); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Ile115= (c.345C>T)?

EPAS1 p.Ile115= (c.345C>T) is associated with Inborn genetic diseases, erythrocytosis, familial, 4 (ClinVar).

How common is EPAS1 p.Ile115= (c.345C>T) in the general population?

EPAS1 p.Ile115= (c.345C>T) is ultra-rare (popmax 0.0691%, eas) (gnomAD).

EPAS1 p.Ile115=

c.345C>T · rs542625493 · VCV898829

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0691%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -0.16, phastCons 1
Overall
CADD	14.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0691% East Asian · 31/44,886 alleles

Filtering AF 0.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0435%

Overall 0.00223% 36/1,614,214 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0691%	1,448
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Admixed American	0.00167%	60,028
European (non-Finnish)	8.47e-05%	1,180,045

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.Ile115=
Coding: c.345C>T
MANE Select: NM_001430
dbSNP: rs542625493
Type: single nucleotide variant
Location: chr2:46356278 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 115: 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

Also linked: erythrocytosis, familial, 4

Similar variants

EPAS1 p.Ile115Val 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.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-ile115 (accessed [today's date]).

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