Is ENTREP3 p.Pro472Leu (c.1415C>T) pathogenic?

ENTREP3 p.Pro472Leu (c.1415C>T) is classified Uncertain significance in ENTREP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.1326); Ultra-rare (popmax 0.0336%, amr).

How common is ENTREP3 p.Pro472Leu (c.1415C>T) in the general population?

ENTREP3 p.Pro472Leu (c.1415C>T) is ultra-rare (popmax 0.0336%, amr) (gnomAD).

What do computational predictors say about ENTREP3 p.Pro472Leu (c.1415C>T)?

AlphaMissense predicts likely benign (score 0.1326) — an in-silico prediction, not a clinical call.

ENTREP3 p.Pro472Leu

c.1415C>T · rs1000466806 · VCV2558803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1326 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1326	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.48	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,092 bp · p 0.33 · regional, not allelic
Overall
CADD	24.6	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 0.0336% Admixed American · 17/50,612 alleles

Filtering AF 0.0214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0175%

Overall 0.0055% 85/1,545,284 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0336%	2,977
Remaining individualsnot grpmax-eligible	0.0134%	7,464
European (non-Finnish)	0.00515%	19,414
South Asian	0.00119%	83,732

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: ENTREP3
Protein: p.Pro472Leu
Coding: c.1415C>T
MANE Select: NM_006589
dbSNP: rs1000466806
Type: single nucleotide variant
Location: chr1:155250371 (GRCh38)
Structure: AlphaFold pLDDT 53.93
Residue 472: the 'disordered' region

Full ENTREP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTREP3 p.Ala229Thr Uncertain significance ★ ⚠ same type
ENTREP3 p.Ala452Thr Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg212Gln Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg212Trp Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg25His Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg371Pro Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg393Gln Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg400Cys 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/entrep3-p-pro472leu (accessed [today's date]).

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