Is ENTREP2 p.Ala533Thr (c.1597G>A) pathogenic?

ENTREP2 p.Ala533Thr (c.1597G>A) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0701); Ultra-rare (popmax 0.084%, mid).

How common is ENTREP2 p.Ala533Thr (c.1597G>A) in the general population?

ENTREP2 p.Ala533Thr (c.1597G>A) is ultra-rare (popmax 0.084%, mid) (gnomAD).

What do computational predictors say about ENTREP2 p.Ala533Thr (c.1597G>A)?

AlphaMissense predicts likely benign (score 0.0701) — an in-silico prediction, not a clinical call.

ENTREP2 p.Ala533Thr

c.1597G>A · rs183167189 · VCV3089198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.084%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0701	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.33	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 -0.64	GERP 0.006
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	7.817	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 0.084% Middle Eastern · 5/5,952 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.0101% 155/1,541,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.084%	1,190
African / African-American	0.0548%	1,824
South Asian	0.0323%	3,094
Remaining individualsnot grpmax-eligible	0.0168%	5,965
European (non-Finnish)	0.00614%	16,280
Admixed American	0.00594%	16,837

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.Ala533Thr
Coding: c.1597G>A
MANE Select: NM_015307
dbSNP: rs183167189
Type: single nucleotide variant
Location: chr15:29123362 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

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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
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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-ala533thr (accessed [today's date]).

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