Is ENTREP1 p.Arg411Cys (c.1231C>T) pathogenic?

ENTREP1 p.Arg411Cys (c.1231C>T) is classified Uncertain significance in ENTREP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: likely benign (0.0727); Very rare (popmax 0.00772%, sas).

How common is ENTREP1 p.Arg411Cys (c.1231C>T) in the general population?

ENTREP1 p.Arg411Cys (c.1231C>T) is very rare (popmax 0.00772%, sas) (gnomAD).

What do computational predictors say about ENTREP1 p.Arg411Cys (c.1231C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

ENTREP1 p.Arg411Cys

c.1231C>T · VCV3275572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00772%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.42	GERP -0.23
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.71 · regional, not allelic
Overall
CADD	13.83	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R258C vs ClinVar R411C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00772% South Asian · 7/90,712 alleles

Filtering AF 0.0036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00256%

Overall 0.0013% 19/1,460,448 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00772%	12,959
Remaining individualsnot grpmax-eligible	0.00321%	31,196
East Asian	0.00224%	44,710
Admixed American	0.00168%	59,516
Finnishnot grpmax-eligible	0.00158%	63,446
European (non-Finnish)	0.000594%	168,456

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: ENTREP1
Protein: p.Arg411Cys
Coding: c.1231C>T
MANE Select: NM_001347995
Type: single nucleotide variant
Location: chr9:69385863 (GRCh38)
Structure: AlphaFold pLDDT 60.47
Residue 411: the 'mediates interaction with epn1' region

Full ENTREP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTREP1 p.Arg411His Likely benign ★ ⚠ same residue
ENTREP1 p.Ala374Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala418Asp Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Thr Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala448Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala492Val Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala574Pro 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/entrep1-p-arg411cys (accessed [today's date]).

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