Is EPOR p.Arg56= (c.168G>T) pathogenic?

EPOR p.Arg56= (c.168G>T) is classified Benign/Likely benign in EPOR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-22). Rare (popmax 0.618%, afr); Associated with primary familial polycythemia due to EPO receptor mutation.

What condition is associated with EPOR p.Arg56= (c.168G>T)?

EPOR p.Arg56= (c.168G>T) is associated with primary familial polycythemia due to EPO receptor mutation (ClinVar).

How common is EPOR p.Arg56= (c.168G>T) in the general population?

EPOR p.Arg56= (c.168G>T) is rare (popmax 0.618%, afr) (gnomAD).

How is Primary familial polycythemia inherited?

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

EPOR p.Arg56=

c.168G>T · rs35977803 · VCV328154

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.618%, afr)

Conditions

primary familial polycythemia due to EPO receptor mutation

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 -1.9	GERP -3.8
Overall
CADD	7.214	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.618% African / African-American · 464/75,058 alleles

Filtering AF 0.572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.553%

Overall 0.0314% 506/1,612,544 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.618%	162
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0288%	3,471
Admixed American	0.0283%	3,531
South Asian	0.0011%	91,074
European (non-Finnish)	0.000254%	393,294

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.Arg56=
Coding: c.168G>T
MANE Select: NM_000121
dbSNP: rs35977803
Type: single nucleotide variant
Location: chr19:11383180 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.74 · 22 PDB
Residue 56: a disulfide bond; a β-strand

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.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
EPOR p.Asn487Ser Benign/Likely 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-arg56 (accessed [today's date]).

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