Is ENTREP3 p.Ala452Thr (c.1354G>A) pathogenic?

ENTREP3 p.Ala452Thr (c.1354G>A) is classified Uncertain significance in ENTREP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely benign (0.0735); Very rare (popmax 0.00263%, sas).

How common is ENTREP3 p.Ala452Thr (c.1354G>A) in the general population?

ENTREP3 p.Ala452Thr (c.1354G>A) is very rare (popmax 0.00263%, sas) (gnomAD).

What do computational predictors say about ENTREP3 p.Ala452Thr (c.1354G>A)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

ENTREP3 p.Ala452Thr

c.1354G>A · VCV3845120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.41	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 0.95	GERP 0.55, phastCons 0.074
Regional constraint	o/e 0.97	unconstrained · MANE · 7,092 bp · p 0.33 · regional, not allelic
Overall
CADD	12.56	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 0.00263% South Asian · 2/76,126 alleles

Filtering AF 0.000845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000684%

Overall 0.00128% 19/1,489,992 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00263%	38,063
Finnishnot grpmax-eligible	0.002%	50,008
European (non-Finnish)	0.00143%	70,064

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.Ala452Thr
Coding: c.1354G>A
MANE Select: NM_006589
Type: single nucleotide variant
Location: chr1:155250432 (GRCh38)
Structure: AlphaFold pLDDT 53.93
Residue 452: 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.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
ENTREP3 p.Arg440Gly 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-ala452thr (accessed [today's date]).

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