Is ENTREP2 p.Pro296Ala (c.886C>G) pathogenic?

ENTREP2 p.Pro296Ala (c.886C>G) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.3656); Ultra-rare (popmax 0.0234%, sas).

How common is ENTREP2 p.Pro296Ala (c.886C>G) in the general population?

ENTREP2 p.Pro296Ala (c.886C>G) is ultra-rare (popmax 0.0234%, sas) (gnomAD).

What do computational predictors say about ENTREP2 p.Pro296Ala (c.886C>G)?

AlphaMissense predicts ambiguous (score 0.3656) — an in-silico prediction, not a clinical call.

ENTREP2 p.Pro296Ala

c.886C>G · rs570961907 · VCV3089218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3656 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, sas)

Computational evidence

Protein change
AlphaMissense	0.3656	ambiguous
REVEL	0.409	indeterminate
SaProt	LLR -12.84	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.78, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	24.1	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 0.0234% South Asian · 19/81,028 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0127%

Overall 0.00548% 84/1,533,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0234%	4,265
Admixed American	0.0228%	4,392
Middle Eastern	0.0168%	5,944
Remaining individualsnot grpmax-eligible	0.0101%	9,915
East Asian	0.00503%	19,873
African / African-American	0.00415%	24,069
European (non-Finnish)	0.00368%	27,175

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.Pro296Ala
Coding: c.886C>G
MANE Select: NM_015307
dbSNP: rs570961907
Type: single nucleotide variant
Location: chr15:29136407 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

ENTREP2 p.Pro296Thr Uncertain significance ★ ⚠ same residue
NSMCE3 p.Gln296= Likely benign ★ same residue
ENTREP2 p.Gly126Ser Uncertain significance ★★ ⚠ same type
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

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-pro296ala (accessed [today's date]).

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