Is ENTREP2 p.Trp458Arg (c.1372T>C) pathogenic?

ENTREP2 p.Trp458Arg (c.1372T>C) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely benign (0.1119); Ultra-rare (popmax 0.0244%, eas).

How common is ENTREP2 p.Trp458Arg (c.1372T>C) in the general population?

ENTREP2 p.Trp458Arg (c.1372T>C) is ultra-rare (popmax 0.0244%, eas) (gnomAD).

What do computational predictors say about ENTREP2 p.Trp458Arg (c.1372T>C)?

AlphaMissense predicts likely benign (score 0.1119) — an in-silico prediction, not a clinical call.

ENTREP2 p.Trp458Arg

c.1372T>C · rs923468122 · VCV3089193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0244%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1119	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -4.15	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 0.008	GERP -0.81, phastCons 0.023
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	9.41	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 0.0244% East Asian · 10/40,926 alleles

Filtering AF 0.0132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.00193% 30/1,551,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0244%	4,093
South Asian	0.019%	5,254
Middle Eastern	0.0166%	6,014
Remaining individualsnot grpmax-eligible	0.00333%	30,050
European (non-Finnish)	8.72e-05%	1,146,992

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.Trp458Arg
Coding: c.1372T>C
MANE Select: NM_015307
dbSNP: rs923468122
Type: single nucleotide variant
Location: chr15:29123587 (GRCh38)
Structure: AlphaFold pLDDT 59.09
Residue 458: the 'disordered' region

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-trp458arg (accessed [today's date]).

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