Is EPAS1 p.Leu332Val (c.994C>G) pathogenic?

EPAS1 p.Leu332Val (c.994C>G) is classified Uncertain significance in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-05). AlphaMissense: likely benign (0.1764); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Leu332Val (c.994C>G)?

EPAS1 p.Leu332Val (c.994C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Leu332Val (c.994C>G) in the general population?

EPAS1 p.Leu332Val (c.994C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about EPAS1 p.Leu332Val (c.994C>G)?

AlphaMissense predicts likely benign (score 0.1764) — an in-silico prediction, not a clinical call.

EPAS1 p.Leu332Val

c.994C>G · rs1236229465 · VCV1768692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1764	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -8.24	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 2.8	GERP -0.68, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 4,474 bp · p 0.11 · regional, not allelic
Overall
CADD	23.8	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 0.00329% South Asian · 3/91,090 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00031% 5/1,614,120 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,932

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.Leu332Val
Coding: c.994C>G
MANE Select: NM_001430
dbSNP: rs1236229465
Type: single nucleotide variant
Location: chr2:46375797 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 332: the pac domain; a turn

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.Leu332= 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
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-leu332val (accessed [today's date]).

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