Is EPAS1 p.Leu836= (c.2508G>A) pathogenic?

EPAS1 p.Leu836= (c.2508G>A) is classified Benign/Likely benign in EPAS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-18). Ultra-rare (popmax 0.0717%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Leu836= (c.2508G>A)?

EPAS1 p.Leu836= (c.2508G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EPAS1 p.Leu836= (c.2508G>A) in the general population?

EPAS1 p.Leu836= (c.2508G>A) is ultra-rare (popmax 0.0717%, amr) (gnomAD).

EPAS1 p.Leu836=

c.2508G>A · rs367846993 · VCV1792346

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0717%, amr)

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 6.8	GERP 1, phastCons 1
Overall
CADD	7.706	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0717% Admixed American · 43/60,006 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.00273% 44/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0717%	1,395
European (non-Finnish)	8.47e-05%	1,180,043

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.Leu836=
Coding: c.2508G>A
MANE Select: NM_001430
dbSNP: rs367846993
Type: single nucleotide variant
Location: chr2:46384555 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 836: the 'ctad' 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.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-leu836 (accessed [today's date]).

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