Is EPOR p.Ala40Val (c.119C>T) pathogenic?

EPOR p.Ala40Val (c.119C>T) is classified Uncertain significance in EPOR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely benign (0.1294); Very rare (popmax 0.00332%, nfe).

How common is EPOR p.Ala40Val (c.119C>T) in the general population?

EPOR p.Ala40Val (c.119C>T) is very rare (popmax 0.00332%, nfe) (gnomAD).

What do computational predictors say about EPOR p.Ala40Val (c.119C>T)?

AlphaMissense predicts likely benign (score 0.1294) — an in-silico prediction, not a clinical call.

EPOR p.Ala40Val

c.119C>T · VCV3389545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1294 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00332%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1294	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,220 bp · p 0.0057 · regional, not allelic
Overall
CADD	27.5	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

Grpmax group 0.00332% European (non-Finnish) · 39/1,172,958 alleles

Filtering AF 0.00249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00218%

Overall 0.00257% 41/1,596,488 alleles · very rare exomes 38/1,444,298 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00332%	30,076
Remaining individualsnot grpmax-eligible	0.00323%	30,958

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.Ala40Val
Coding: c.119C>T
MANE Select: NM_000121
Type: single nucleotide variant
Location: chr19:11383229 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.74 · 22 PDB
Residue 40: an α-helix

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

Similar variants

EPOR p.Trp439Ter Pathogenic ★★ same type
EPOR p.Glu292Lys Uncertain significance ★★ ⚠ same type
EPOR p.Pro327Leu Uncertain significance ★★ ⚠ same type
EPOR c.115+7A>G Benign/Likely benign ★★ same type
EPOR c.-55G>A Benign ★★ same type
EPOR c.*35G>A Benign ★★ same type
EPOR p.Ala186= Benign/Likely benign ★★ same type
EPOR p.Ala219= Benign ★★ same type

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-ala40val (accessed [today's date]).

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