Is ENTREP2 p.Pro243Arg (c.728C>G) pathogenic?

ENTREP2 p.Pro243Arg (c.728C>G) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-26). AlphaMissense: likely pathogenic (0.952); Ultra-rare (popmax 0.0182%, mid).

How common is ENTREP2 p.Pro243Arg (c.728C>G) in the general population?

ENTREP2 p.Pro243Arg (c.728C>G) is ultra-rare (popmax 0.0182%, mid) (gnomAD).

What do computational predictors say about ENTREP2 p.Pro243Arg (c.728C>G)?

AlphaMissense predicts likely pathogenic (score 0.952) — an in-silico prediction, not a clinical call.

ENTREP2 p.Pro243Arg

c.728C>G · rs748122982 · VCV3089214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.952	likely pathogenic
REVEL	0.456	indeterminate
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	28.6	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 0.0182% Middle Eastern · 1/5,494 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000453%

Overall 0.0013% 19/1,465,600 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0182%	5,494
Admixed American	0.00645%	15,505
East Asian	0.00291%	34,376
South Asian	0.0029%	34,436
African / African-American	0.00149%	67,168
European (non-Finnish)	0.00107%	93,047

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.Pro243Arg
Coding: c.728C>G
MANE Select: NM_015307
dbSNP: rs748122982
Type: single nucleotide variant
Location: chr15:29137097 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

ENTREP2 p.Pro243Gln Uncertain significance ★ ⚠ same residue
NSMCE3 p.Pro243= 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

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-pro243arg (accessed [today's date]).

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