Is EPO p.Ser18Leu (c.53C>T) pathogenic?

EPO p.Ser18Leu (c.53C>T) is classified Likely benign in EPO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0613); Very rare (popmax 0.00559%, nfe).

How common is EPO p.Ser18Leu (c.53C>T) in the general population?

EPO p.Ser18Leu (c.53C>T) is very rare (popmax 0.00559%, nfe) (gnomAD).

What do computational predictors say about EPO p.Ser18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

EPO p.Ser18Leu

c.53C>T · VCV4664894

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00559%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -2.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP -1.6, phastCons 0.99
Overall
CADD	3.586	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 0.00559% European (non-Finnish) · 66/1,180,028 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00428% 69/1,613,868 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00559%	17,879
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00157%	63,868
African / African-American	0.00133%	74,916

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.Ser18Leu
Coding: c.53C>T
MANE Select: NM_003254 · reported on NM_000799
Type: single nucleotide variant
Location: chr7:100721597 (GRCh38)
Structure: AlphaFold pLDDT 90.09 · 13 PDB

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

Similar variants

EPO p.Ser18= Benign/Likely benign ★★ same residue
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

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-ser18leu (accessed [today's date]).

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