Is ENTREP2 p.Pro297Leu (c.890C>T) pathogenic?

ENTREP2 p.Pro297Leu (c.890C>T) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-26). AlphaMissense: ambiguous (0.4959); Very rare (popmax 0.00371%, sas).

How common is ENTREP2 p.Pro297Leu (c.890C>T) in the general population?

ENTREP2 p.Pro297Leu (c.890C>T) is very rare (popmax 0.00371%, sas) (gnomAD).

What do computational predictors say about ENTREP2 p.Pro297Leu (c.890C>T)?

AlphaMissense predicts ambiguous (score 0.4959) — an in-silico prediction, not a clinical call.

ENTREP2 p.Pro297Leu

c.890C>T · rs1475014128 · VCV2479866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00371%, sas)

Computational evidence

Protein change
AlphaMissense	0.4959	ambiguous
REVEL	0.458	indeterminate
SaProt	LLR -12.46	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	27.3	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 0.00371% South Asian · 3/80,942 alleles

Filtering AF 0.000984% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000473%

Overall 0.00117% 18/1,533,464 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0178%	5,624
South Asiangrpmax	0.00371%	26,981
European (non-Finnish)	0.000438%	228,313

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro297Leu
Coding: c.890C>T
MANE Select: NM_015307
dbSNP: rs1475014128
Type: single nucleotide variant
Location: chr15:29136403 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

NSMCE3 p.Pro297Ser Uncertain significance ★ ⚠ 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
NSMCE3 p.Ile193Val 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-pro297leu (accessed [today's date]).

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