Is ENTREP2 p.His227Gln (c.681C>G) pathogenic?

ENTREP2 p.His227Gln (c.681C>G) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-11). AlphaMissense: likely benign (0.1516); Very rare (popmax 0.0014%, sas).

How common is ENTREP2 p.His227Gln (c.681C>G) in the general population?

ENTREP2 p.His227Gln (c.681C>G) is very rare (popmax 0.0014%, sas) (gnomAD).

What do computational predictors say about ENTREP2 p.His227Gln (c.681C>G)?

AlphaMissense predicts likely benign (score 0.1516) — an in-silico prediction, not a clinical call.

ENTREP2 p.His227Gln

c.681C>G · rs61741714 · VCV3089213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1516 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0014%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1516	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.69	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 -2.6	GERP -3.7
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	1.183	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 0.0014% South Asian · 1/71,270 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000226% 3/1,327,954 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0014%	71,270
European (non-Finnish)	0.000178%	560,576

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.His227Gln
Coding: c.681C>G
MANE Select: NM_015307
dbSNP: rs61741714
Type: single nucleotide variant
Location: chr15:29137144 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

NSMCE3 p.Phe227= Likely benign ★★ 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.Glu45Gln 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-his227gln (accessed [today's date]).

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