Is ENTREP2 p.Ser418Trp (c.1253C>G) pathogenic?

ENTREP2 p.Ser418Trp (c.1253C>G) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1218); Ultra-rare (popmax 0.0262%, sas).

How common is ENTREP2 p.Ser418Trp (c.1253C>G) in the general population?

ENTREP2 p.Ser418Trp (c.1253C>G) is ultra-rare (popmax 0.0262%, sas) (gnomAD).

What do computational predictors say about ENTREP2 p.Ser418Trp (c.1253C>G)?

AlphaMissense predicts likely benign (score 0.1218) — an in-silico prediction, not a clinical call.

ENTREP2 p.Ser418Trp

c.1253C>G · VCV3275579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0262%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1218	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.20	donor loss, 50 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.099	GERP -2.4
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	16.07	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0262% South Asian · 22/84,062 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00264% 41/1,550,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0262%	3,821
Remaining individualsnot grpmax-eligible	0.00499%	20,034
European (non-Finnish)	0.00139%	71,686

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.Ser418Trp
Coding: c.1253C>G
MANE Select: NM_015307
Type: single nucleotide variant
Location: chr15:29124737 (GRCh38)
Structure: AlphaFold pLDDT 59.09
Residue 418: 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
NSMCE3 p.Ile193Val 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-ser418trp (accessed [today's date]).

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