Is EPOR p.Pro502Arg (c.1505C>G) pathogenic?

EPOR p.Pro502Arg (c.1505C>G) is classified Conflicting classifications of pathogenicity in EPOR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-07). AlphaMissense: likely benign (0.0722); Ultra-rare (popmax 0.0891%, eas); Associated with primary familial polycythemia due to EPO receptor mutation.

What condition is associated with EPOR p.Pro502Arg (c.1505C>G)?

EPOR p.Pro502Arg (c.1505C>G) is associated with primary familial polycythemia due to EPO receptor mutation (ClinVar).

How common is EPOR p.Pro502Arg (c.1505C>G) in the general population?

EPOR p.Pro502Arg (c.1505C>G) is ultra-rare (popmax 0.0891%, eas) (gnomAD).

How is Primary familial polycythemia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EPOR p.Pro502Arg (c.1505C>G)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

EPOR p.Pro502Arg

c.1505C>G · VCV3380582

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary familial polycythemia due to EPO receptor mutation

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -7.53	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	GERP -0.6, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 6,220 bp · p 0.0057 · regional, not allelic
Overall
CADD	19.31	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 0.0891% East Asian · 40/44,886 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0596%

Overall 0.00328% 53/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0891%	1,122
South Asian	0.00769%	13,011
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.000169%	590,012

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: EPOR
Protein: p.Pro502Arg
Coding: c.1505C>G
MANE Select: NM_000121
Type: single nucleotide variant
Location: chr19:11378006 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.74 · 22 PDB

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

Disease context

primary familial polycythemia due to EPO receptor mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary familial polycythemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

EPOR p.Pro502Ser Uncertain significance ★ ⚠ same residue
EPOR p.Trp439Ter Pathogenic ★★ same condition
EPOR p.Pro327Leu Uncertain significance ★★ ⚠ same condition
EPOR c.115+7A>G Benign/Likely benign ★★ same condition
EPOR c.-55G>A Benign ★★ same condition
EPOR c.*35G>A Benign ★★ same condition
EPOR p.Ala186= Benign/Likely benign ★★ same condition
EPOR p.Ala219= Benign ★★ 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/epor-p-pro502arg (accessed [today's date]).

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