Is ENTREP3 p.Cys136Gly (c.406T>G) pathogenic?

ENTREP3 p.Cys136Gly (c.406T>G) is classified Uncertain significance in ENTREP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-30). AlphaMissense: likely pathogenic (0.9363); Absent from gnomAD v4.1.

How common is ENTREP3 p.Cys136Gly (c.406T>G) in the general population?

ENTREP3 p.Cys136Gly (c.406T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENTREP3 p.Cys136Gly (c.406T>G)?

AlphaMissense predicts likely pathogenic (score 0.9363) — an in-silico prediction, not a clinical call.

ENTREP3 p.Cys136Gly

c.406T>G · VCV3275581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9363 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9363	likely pathogenic · top 7% in ENTREP3
REVEL	0.34	indeterminate
SaProt	LLR -17.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,092 bp · p 0.33 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENTREP3
Protein: p.Cys136Gly
Coding: c.406T>G
MANE Select: NM_006589
Type: single nucleotide variant
Location: chr1:155253966 (GRCh38)
Structure: AlphaFold pLDDT 53.93

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

Similar variants

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
ENTREP3 p.Arg400Cys 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-cys136gly (accessed [today's date]).

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