Is ENTREP2 p.Leu45Phe (c.133C>T) pathogenic?

ENTREP2 p.Leu45Phe (c.133C>T) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.4132); Very rare (popmax 0.00127%, sas).

How common is ENTREP2 p.Leu45Phe (c.133C>T) in the general population?

ENTREP2 p.Leu45Phe (c.133C>T) is very rare (popmax 0.00127%, sas) (gnomAD).

What do computational predictors say about ENTREP2 p.Leu45Phe (c.133C>T)?

AlphaMissense predicts ambiguous (score 0.4132) — an in-silico prediction, not a clinical call.

ENTREP2 p.Leu45Phe

c.133C>T · VCV4249403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4132	ambiguous
REVEL	0.102	moderately benign-leaning
SaProt	LLR -8.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP -2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	26.4	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 0.00127% South Asian · 1/78,600 alleles

Overall 7.61e-05% 1/1,314,870 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: ENTREP2
Protein: p.Leu45Phe
Coding: c.133C>T
MANE Select: NM_015307
Type: single nucleotide variant
Location: chr15:29570591 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

NSMCE3 p.Glu45Gln Uncertain significance ★★ ⚠ same residue
NSMCE3 p.Glu45Lys 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.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-leu45phe (accessed [today's date]).

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