Is EPAS1 p.Val700Ile (c.2098G>A) pathogenic?

EPAS1 p.Val700Ile (c.2098G>A) is classified Conflicting classifications of pathogenicity in EPAS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-09). AlphaMissense: likely benign (0.0661); Very rare (popmax 0.00833%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Val700Ile (c.2098G>A)?

EPAS1 p.Val700Ile (c.2098G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Val700Ile (c.2098G>A) in the general population?

EPAS1 p.Val700Ile (c.2098G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about EPAS1 p.Val700Ile (c.2098G>A)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

EPAS1 p.Val700Ile

c.2098G>A · rs1456606052 · VCV1785828

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -7.86	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 0.28	GERP -3.1, phastCons 0.27
Regional constraint	o/e 1.18	unconstrained · MANE · 4,363 bp · p 0.00029 · regional, not allelic
Overall
CADD	4.039	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 0.00833% Admixed American · 5/60,008 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,613,914 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.Val700Ile
Coding: c.2098G>A
MANE Select: NM_001430
dbSNP: rs1456606052
Type: single nucleotide variant
Location: chr2:46381648 (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

Similar variants

EPAS1 p.Val700Ala Uncertain significance ★ ⚠ same residue
EPAS1 p.Val700= Likely benign ★ 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

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-val700ile (accessed [today's date]).

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