Is EPO p.Ala138Val (c.413C>T) pathogenic?

EPO p.Ala138Val (c.413C>T) is classified Uncertain significance in EPO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.0921); Very rare (popmax 0.00134%, afr).

How common is EPO p.Ala138Val (c.413C>T) in the general population?

EPO p.Ala138Val (c.413C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about EPO p.Ala138Val (c.413C>T)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

EPO p.Ala138Val

c.413C>T · VCV4018934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.76	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 -0.18	GERP -3
Overall
CADD	12.91	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 0.00134% African / African-American · 1/74,856 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,612,998 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,856
South Asian	0.0011%	91,010
European (non-Finnish)	0.00017%	589,880

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: EPO
Protein: p.Ala138Val
Coding: c.413C>T
MANE Select: NM_003254 · reported on NM_000799
Type: single nucleotide variant
Location: chr7:100722830 (GRCh38)
Structure: AlphaFold pLDDT 90.09 · 13 PDB
Residue 138: a disulfide bond; the ntr domain; an α-helix

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

Similar variants

EPO c.14-1G>C Uncertain significance ★★ same type
EPO c.13+10C>T Benign/Likely benign ★★ same type
EPO c.247-66G>A Benign ★★ same type
EPO p.Ala151= Benign ★★ same type
EPO p.Ala57= Likely benign ★★ same type
EPO p.Ala87= Likely benign ★★ same type
EPO p.Asp70Asn Likely benign ★★ same type
EPO p.Lys79= Benign/Likely 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/epo-p-ala138val (accessed [today's date]).

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