Is EPOR p.Pro502Ser (c.1504C>T) pathogenic?

EPOR p.Pro502Ser (c.1504C>T) is classified Uncertain significance in EPOR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.0753); Absent from gnomAD v4.1; Associated with primary familial polycythemia due to EPO receptor mutation.

What condition is associated with EPOR p.Pro502Ser (c.1504C>T)?

EPOR p.Pro502Ser (c.1504C>T) is associated with primary familial polycythemia due to EPO receptor mutation (ClinVar).

How common is EPOR p.Pro502Ser (c.1504C>T) in the general population?

EPOR p.Pro502Ser (c.1504C>T) is absent from gnomAD v4.1 (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.Pro502Ser (c.1504C>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

EPOR p.Pro502Ser

c.1504C>T · VCV4685763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary familial polycythemia due to EPO receptor mutation

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.02	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 4.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,220 bp · p 0.0057 · regional, not allelic
Overall
CADD	20.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPOR
Protein: p.Pro502Ser
Coding: c.1504C>T
MANE Select: NM_000121
Type: single nucleotide variant
Location: chr19:11378007 (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.Pro502Arg Conflicting classifications of pathogenicity ★ ⚠ 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-pro502ser (accessed [today's date]).

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