Is ENTREP1 p.Pro412Thr (c.1234C>A) pathogenic?

ENTREP1 p.Pro412Thr (c.1234C>A) is classified Uncertain significance in ENTREP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-07). AlphaMissense: likely benign (0.0737); Very rare (popmax 8.48e-05%, nfe).

How common is ENTREP1 p.Pro412Thr (c.1234C>A) in the general population?

ENTREP1 p.Pro412Thr (c.1234C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ENTREP1 p.Pro412Thr (c.1234C>A)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

ENTREP1 p.Pro412Thr

c.1234C>A · rs1834014017 · VCV2534898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.35	donor gain · deltas
Pangolin	Δ0.22	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	GERP 1.7, phastCons 0.027
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.71 · regional, not allelic
Overall
CADD	13.47	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P259T vs ClinVar P412T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,098 alleles

Overall 6.85e-05% 1/1,460,562 alleles · very rare

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: ENTREP1
Protein: p.Pro412Thr
Coding: c.1234C>A
MANE Select: NM_001347995
dbSNP: rs1834014017
Type: single nucleotide variant
Location: chr9:69385866 (GRCh38)
Structure: AlphaFold pLDDT 60.47
Residue 412: the 'mediates interaction with epn1' region

Full ENTREP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTREP1 p.Ala374Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala418Asp Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Thr Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala448Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala492Val Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala574Pro Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala588Val Conflicting classifications of pathogenicity ★ ⚠ 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/entrep1-p-pro412thr (accessed [today's date]).

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