Is ENTREP3 p.Pro455Leu (c.1364C>T) pathogenic?

ENTREP3 p.Pro455Leu (c.1364C>T) is classified Uncertain significance in ENTREP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-07). AlphaMissense: likely benign (0.0933); Ultra-rare (popmax 0.0135%, nfe).

How common is ENTREP3 p.Pro455Leu (c.1364C>T) in the general population?

ENTREP3 p.Pro455Leu (c.1364C>T) is ultra-rare (popmax 0.0135%, nfe) (gnomAD).

What do computational predictors say about ENTREP3 p.Pro455Leu (c.1364C>T)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

ENTREP3 p.Pro455Leu

c.1364C>T · VCV3508791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Pangolin	Δ0.33	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.5	GERP 0.47, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,092 bp · p 0.33 · regional, not allelic
Overall
CADD	17.81	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 0.0135% European (non-Finnish) · 152/1,122,606 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0106% 159/1,496,630 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0135%	7,386
Remaining individualsnot grpmax-eligible	0.0121%	8,252

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.Pro455Leu
Coding: c.1364C>T
MANE Select: NM_006589
Type: single nucleotide variant
Location: chr1:155250422 (GRCh38)
Structure: AlphaFold pLDDT 53.93
Residue 455: 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-pro455leu (accessed [today's date]).

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