Is EPOR p.Arg437His (c.1310G>A) pathogenic?

EPOR p.Arg437His (c.1310G>A) is classified Conflicting classifications of pathogenicity in EPOR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.0682); Rare (popmax 0.653%, afr); Associated with primary familial polycythemia due to EPO receptor mutation.

What condition is associated with EPOR p.Arg437His (c.1310G>A)?

EPOR p.Arg437His (c.1310G>A) is associated with primary familial polycythemia due to EPO receptor mutation (ClinVar).

How common is EPOR p.Arg437His (c.1310G>A) in the general population?

EPOR p.Arg437His (c.1310G>A) is rare (popmax 0.653%, afr) (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.Arg437His (c.1310G>A)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

EPOR p.Arg437His

c.1310G>A · rs62638744 · VCV268129

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.653%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary familial polycythemia due to EPO receptor mutation

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.56	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 0.73	GERP -1.4
Regional constraint	o/e 0.89	unconstrained · MANE · 6,220 bp · p 0.0057 · regional, not allelic
Overall
CADD	12.31	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 0.653% African / African-American · 490/75,012 alleles

Filtering AF 0.605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.586%

Overall 0.0821% 1,325/1,614,070 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.653%	153
Middle Eastern	0.561%	178
Remaining individualsnot grpmax-eligible	0.187%	534
Admixed American	0.183%	545
European (non-Finnish)	0.0478%	2,092
South Asian	0.00769%	13,012
East Asian	0.00668%	14,963

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.Arg437His
Coding: c.1310G>A
MANE Select: NM_000121
dbSNP: rs62638744
Type: single nucleotide variant
Location: chr19:11378201 (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.Arg437Cys 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-arg437his (accessed [today's date]).

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