Is EPAS1 p.Asn522Ser (c.1565A>G) pathogenic?

EPAS1 p.Asn522Ser (c.1565A>G) is classified Uncertain significance in EPAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0544); Ultra-rare (popmax 0.0869%, eas).

How common is EPAS1 p.Asn522Ser (c.1565A>G) in the general population?

EPAS1 p.Asn522Ser (c.1565A>G) is ultra-rare (popmax 0.0869%, eas) (gnomAD).

What do computational predictors say about EPAS1 p.Asn522Ser (c.1565A>G)?

AlphaMissense predicts likely benign (score 0.0544) — an in-silico prediction, not a clinical call.

EPAS1 p.Asn522Ser

c.1565A>G · VCV4693461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0544 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0869%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0544	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -3.83	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 4.7	GERP -1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 4,474 bp · p 0.11 · regional, not allelic
Overall
CADD	16.4	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 0.0869% East Asian · 39/44,890 alleles

Filtering AF 0.0653% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00378% 61/1,611,720 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0869%	1,151
Middle Eastern	0.0164%	6,084
African / African-American	0.00267%	37,445
South Asian	0.0022%	45,544
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.00127%	78,666

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.Asn522Ser
Coding: c.1565A>G
MANE Select: NM_001430
Type: single nucleotide variant
Location: chr2:46380237 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 522: the 'ntad' region

Full EPAS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPAS1 p.Asn522Asp Uncertain significance ★ ⚠ same residue
EPAS1 p.Asn522Lys Uncertain significance ★ ⚠ same residue
EPAS1 p.Asn522Tyr Uncertain significance ★ ⚠ same residue
EPAS1 p.Gly537Arg Pathogenic ★★ same type
EPAS1 p.Met535Thr Pathogenic ★★ ⚠ same type
EPAS1 c.-231C>G Uncertain significance ★★ same type
EPAS1 p.Ala439Gly Uncertain significance ★★ ⚠ same type
EPAS1 p.Ala463Thr Uncertain significance ★★ ⚠ same type

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-asn522ser (accessed [today's date]).

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