Is EPN3 p.Arg375Ser (c.1125G>T) pathogenic?

EPN3 p.Arg375Ser (c.1125G>T) is classified Uncertain significance in EPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-31). AlphaMissense: likely benign (0.1962); Ultra-rare (popmax 0.024%, afr).

How common is EPN3 p.Arg375Ser (c.1125G>T) in the general population?

EPN3 p.Arg375Ser (c.1125G>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about EPN3 p.Arg375Ser (c.1125G>T)?

AlphaMissense predicts likely benign (score 0.1962) — an in-silico prediction, not a clinical call.

EPN3 p.Arg375Ser

c.1125G>T · rs139675779 · VCV3089769

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1962 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1962	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -3.58	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,597 bp · p 0.012 · regional, not allelic
Overall
CADD	22.0	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 0.024% African / African-American · 18/75,028 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00136% 22/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,168
Remaining individualsnot grpmax-eligible	0.0048%	20,832
Admixed American	0.00167%	60,032

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.Arg375Ser
Coding: c.1125G>T
MANE Select: NM_017957
dbSNP: rs139675779
Type: single nucleotide variant
Location: chr17:50540938 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01
Residue 375: the '5 x 3 aa repeats of [de]-p-w' region; the 'disordered' region

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

Similar variants

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
EPN3 p.Ala541Glu 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-arg375ser (accessed [today's date]).

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