Is ENTREP2 p.Ile189Val (c.565A>G) pathogenic?

ENTREP2 p.Ile189Val (c.565A>G) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0888); Ultra-rare (popmax 0.0125%, nfe).

How common is ENTREP2 p.Ile189Val (c.565A>G) in the general population?

ENTREP2 p.Ile189Val (c.565A>G) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about ENTREP2 p.Ile189Val (c.565A>G)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

ENTREP2 p.Ile189Val

c.565A>G · VCV4249400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.12	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 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	22.9	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 0.0125% European (non-Finnish) · 143/1,146,986 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00967% 150/1,551,340 alleles · ultra-rare exomes 144/1,399,284 · genomes 6/152,056 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,021
Remaining individualsnot grpmax-eligible	0.00665%	15,030
Admixed American	0.00392%	25,489
African / African-American	0.00137%	73,014

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.Ile189Val
Coding: c.565A>G
MANE Select: NM_015307
Type: single nucleotide variant
Location: chr15:29151799 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

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NSMCE3 p.Gln14His Uncertain significance ★★ ⚠ same type
NSMCE3 p.Glu45Gln Uncertain significance ★★ ⚠ same type
NSMCE3 p.Gly78Arg Uncertain significance ★★ ⚠ same type
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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-ile189val (accessed [today's date]).

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