Is ENTREP2 p.Ala196Val (c.587C>T) pathogenic?

ENTREP2 p.Ala196Val (c.587C>T) is classified Uncertain significance in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: ambiguous (0.3703); Very rare (popmax 0.00724%, nfe).

How common is ENTREP2 p.Ala196Val (c.587C>T) in the general population?

ENTREP2 p.Ala196Val (c.587C>T) is very rare (popmax 0.00724%, nfe) (gnomAD).

What do computational predictors say about ENTREP2 p.Ala196Val (c.587C>T)?

AlphaMissense predicts ambiguous (score 0.3703) — an in-silico prediction, not a clinical call.

ENTREP2 p.Ala196Val

c.587C>T · VCV3845103

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00724%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3703	ambiguous
REVEL	0.287	benign-leaning
SaProt	LLR -5.02	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 12	GERP 0.84, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 447 kb · p 0.2 · regional, not allelic
Overall
CADD	26.2	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 0.00724% European (non-Finnish) · 83/1,147,016 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00548%

Overall 0.0058% 90/1,551,564 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00724%	13,819
Remaining individualsnot grpmax-eligible	0.00665%	15,038
African / African-American	0.00274%	36,528
Admixed American	0.00196%	50,988

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.Ala196Val
Coding: c.587C>T
MANE Select: NM_015307
Type: single nucleotide variant
Location: chr15:29151777 (GRCh38)
Structure: AlphaFold pLDDT 59.09

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

Similar variants

NSMCE3 p.Thr196Ala 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.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-ala196val (accessed [today's date]).

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