Is ENTREP2 p.Pro296Thr (c.886C>A) pathogenic?

ENTREP2 p.Pro296Thr (c.886C>A) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely pathogenic (0.7012); Ultra-rare (popmax 0.0111%, sas).

How common is ENTREP2 p.Pro296Thr (c.886C>A) in the general population?

ENTREP2 p.Pro296Thr (c.886C>A) is ultra-rare (popmax 0.0111%, sas) (gnomAD).

What do computational predictors say about ENTREP2 p.Pro296Thr (c.886C>A)?

AlphaMissense predicts likely pathogenic (score 0.7012) — an in-silico prediction, not a clinical call.

ENTREP2 p.Pro296Thr

c.886C>A · rs570961907 · VCV3089217

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7012	likely pathogenic
REVEL	0.426	indeterminate
SaProt	LLR -14.60	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0111% South Asian · 9/81,032 alleles

Filtering AF 0.0059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00543%

Overall 0.00639% 98/1,533,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0111%	9,004
European (non-Finnish)	0.00718%	13,919
Remaining individualsnot grpmax-eligible	0.00504%	19,822
African / African-American	0.00277%	36,043
East Asian	0.00252%	39,758
Finnishnot grpmax-eligible	0.00177%	56,608

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.Pro296Thr
Coding: c.886C>A
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.Pro296Ala 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-pro296thr (accessed [today's date]).

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