Is ENTREP2 p.Gly126Ser (c.376G>A) pathogenic?

ENTREP2 p.Gly126Ser (c.376G>A) is classified Uncertain significance in ENTREP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-27). AlphaMissense: likely benign (0.0958); Rare (popmax 0.117%, eas); Associated with congenital portosystemic shunt.

What condition is associated with ENTREP2 p.Gly126Ser (c.376G>A)?

ENTREP2 p.Gly126Ser (c.376G>A) is associated with congenital portosystemic shunt (ClinVar).

How common is ENTREP2 p.Gly126Ser (c.376G>A) in the general population?

ENTREP2 p.Gly126Ser (c.376G>A) is rare (popmax 0.117%, eas) (gnomAD).

What do computational predictors say about ENTREP2 p.Gly126Ser (c.376G>A)?

AlphaMissense predicts likely benign (score 0.0958) — an in-silico prediction, not a clinical call.

ENTREP2 p.Gly126Ser

c.376G>A · VCV3845106

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0958 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital portosystemic shunt

Computational evidence

Protein change
AlphaMissense	0.0958	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -3.66	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 4.8	GERP 0.81, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	23.6	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 0.117% East Asian · 48/40,872 alleles

Filtering AF 0.0909% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0816%

Overall 0.00323% 50/1,549,514 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.117%	851
Remaining individualsnot grpmax-eligible	0.00167%	60,042
South Asian	0.00119%	83,908

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: ENTREP2
Protein: p.Gly126Ser
Coding: c.376G>A
MANE Select: NM_015307
Type: single nucleotide variant
Location: chr15:29252379 (GRCh38)
Structure: AlphaFold pLDDT 59.09

Full ENTREP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital portosystemic shunt — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ENTREP2 p.Val83Ile Uncertain significance ★ ⚠ same condition
NSMCE3 p.Ala293Thr Uncertain significance ★★ ⚠ same type
NSMCE3 p.Arg133Ser Uncertain significance ★★ ⚠ same type
NSMCE3 p.Gln14His Uncertain significance ★★ ⚠ same type
NSMCE3 p.Glu45Gln Uncertain significance ★★ ⚠ same type
NSMCE3 p.Gly78Arg Uncertain significance ★★ ⚠ same type
NSMCE3 p.Ile193Val Uncertain significance ★★ ⚠ same type
NSMCE3 p.Pro65Leu 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/entrep2-p-gly126ser (accessed [today's date]).

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