Is EPOR p.Ala99Val (c.296C>T) pathogenic?

EPOR p.Ala99Val (c.296C>T) is classified Conflicting classifications of pathogenicity in EPOR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-27). AlphaMissense: likely benign (0.0909); Rare (popmax 0.181%, nfe); Associated with primary familial polycythemia due to EPO receptor mutation.

What condition is associated with EPOR p.Ala99Val (c.296C>T)?

EPOR p.Ala99Val (c.296C>T) is associated with primary familial polycythemia due to EPO receptor mutation (ClinVar).

How common is EPOR p.Ala99Val (c.296C>T) in the general population?

EPOR p.Ala99Val (c.296C>T) is rare (popmax 0.181%, nfe) (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.Ala99Val (c.296C>T)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

EPOR p.Ala99Val

c.296C>T · rs146235694 · VCV713659

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary familial polycythemia due to EPO receptor mutation

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -8.95	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 2.1	GERP -0.46, phastCons 0.41
Regional constraint	o/e 0.89	unconstrained · MANE · 6,220 bp · p 0.0057 · regional, not allelic
Overall
CADD	15.69	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 0.181% European (non-Finnish) · 2,139/1,180,008 alleles

Filtering AF 0.175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.172%

Overall 0.149% 2,402/1,614,122 alleles · rare exomes 2,253/1,461,774 · genomes 149/152,348 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.181%	552
Remaining individualsnot grpmax-eligible	0.173%	579
Admixed American	0.133%	750
Ashkenazi Jewishnot grpmax-eligible	0.098%	1,021
Finnishnot grpmax-eligible	0.0391%	2,560
African / African-American	0.0266%	3,753
South Asian	0.0011%	91,078

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.Ala99Val
Coding: c.296C>T
MANE Select: NM_000121
dbSNP: rs146235694
Type: single nucleotide variant
Location: chr19:11382061 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.74 · 22 PDB
Residue 99: a turn

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.Arg56= 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-ala99val (accessed [today's date]).

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