Is ENTREP3 p.Arg653Cys (c.1957C>T) pathogenic?

ENTREP3 p.Arg653Cys (c.1957C>T) is classified Uncertain significance in ENTREP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: likely benign (0.2247); Very rare (popmax 0.00721%, eas).

How common is ENTREP3 p.Arg653Cys (c.1957C>T) in the general population?

ENTREP3 p.Arg653Cys (c.1957C>T) is very rare (popmax 0.00721%, eas) (gnomAD).

What do computational predictors say about ENTREP3 p.Arg653Cys (c.1957C>T)?

AlphaMissense predicts likely benign (score 0.2247) — an in-silico prediction, not a clinical call.

ENTREP3 p.Arg653Cys

c.1957C>T · rs539290757 · VCV2615303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00721%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2247	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -8.93	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,092 bp · p 0.33 · regional, not allelic
Overall
CADD	31.0	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 0.00721% East Asian · 3/41,582 alleles

Filtering AF 0.00191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00103%

Overall 0.00168% 25/1,484,500 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00721%	13,861
Remaining individualsnot grpmax-eligible	0.00526%	19,010
Finnishnot grpmax-eligible	0.00175%	57,198
European (non-Finnish)	0.00152%	65,713
South Asian	0.00139%	71,940

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: ENTREP3
Protein: p.Arg653Cys
Coding: c.1957C>T
MANE Select: NM_006589
dbSNP: rs539290757
Type: single nucleotide variant
Location: chr1:155247832 (GRCh38)
Structure: AlphaFold pLDDT 53.93
Residue 653: the 'disordered' region

Full ENTREP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTREP3 p.Arg653His Uncertain significance ★ ⚠ same residue
ENTREP3 p.Ala229Thr Uncertain significance ★ ⚠ same type
ENTREP3 p.Ala452Thr Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg212Gln Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg212Trp Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg25His Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg371Pro Uncertain significance ★ ⚠ same type
ENTREP3 p.Arg393Gln 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/entrep3-p-arg653cys (accessed [today's date]).

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