Is EPN3 p.Ser18= (c.54C>T) pathogenic?

EPN3 p.Ser18= (c.54C>T) is classified Likely benign in EPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). Ultra-rare (popmax 0.0347%, afr).

How common is EPN3 p.Ser18= (c.54C>T) in the general population?

EPN3 p.Ser18= (c.54C>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

EPN3 p.Ser18=

c.54C>T · VCV4250106

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.7
Overall
CADD	0.223	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0347% African / African-American · 26/74,916 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00421% 68/1,613,928 alleles · ultra-rare exomes 51/1,461,782 · genomes 17/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,881
Finnishnot grpmax-eligible	0.0125%	7,995
South Asian	0.00659%	15,180
European (non-Finnish)	0.00237%	42,144

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: EPN3
Protein: p.Ser18=
Coding: c.54C>T
MANE Select: NM_017957
Type: single nucleotide variant
Location: chr17:50536610 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01
Residue 18: the enth domain

Full EPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN3 p.Ser18Pro Uncertain significance ★ ⚠ same residue
EPN3 p.Ala244Val Uncertain significance ★ ⚠ same type
EPN3 p.Ala267Thr Uncertain significance ★ ⚠ same type
EPN3 p.Ala270Gly Uncertain significance ★ ⚠ same type
EPN3 p.Ala334Ser Uncertain significance ★ ⚠ same type
EPN3 p.Ala334Thr Uncertain significance ★ ⚠ same type
EPN3 p.Ala390Val Uncertain significance ★ ⚠ same type
EPN3 p.Ala492Val Uncertain significance ★ ⚠ 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/epn3-p-ser18 (accessed [today's date]).

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