Is EPAS1 p.Pro465Ala (c.1393C>G) pathogenic?

EPAS1 p.Pro465Ala (c.1393C>G) is classified Uncertain significance in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-09). AlphaMissense: likely benign (0.0577); Very rare (popmax 0.00034%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Pro465Ala (c.1393C>G)?

EPAS1 p.Pro465Ala (c.1393C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Pro465Ala (c.1393C>G) in the general population?

EPAS1 p.Pro465Ala (c.1393C>G) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about EPAS1 p.Pro465Ala (c.1393C>G)?

AlphaMissense predicts likely benign (score 0.0577) — an in-silico prediction, not a clinical call.

EPAS1 p.Pro465Ala

c.1393C>G · rs2546473666 · VCV2565057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0577 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0577	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.09	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 0.47	GERP -3
Regional constraint	o/e 1.10	unconstrained · MANE · 4,474 bp · p 0.11 · regional, not allelic
Overall
CADD	7.838	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00034% European (non-Finnish) · 4/1,177,180 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000275% 4/1,453,324 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.Pro465Ala
Coding: c.1393C>G
MANE Select: NM_001430
dbSNP: rs2546473666
Type: single nucleotide variant
Location: chr2:46378037 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 465: 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.Pro465= Likely benign ★★ same residue
EPAS1 p.Pro465Arg Uncertain significance ★ ⚠ same residue
EPAS1 p.Pro465Gln Uncertain significance ★ ⚠ same residue
EPAS1 p.Pro465Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EPAS1 p.Pro465Thr 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

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-pro465ala (accessed [today's date]).

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