Is ENTREP1 p.Arg416Gln (c.1247G>A) pathogenic?

ENTREP1 p.Arg416Gln (c.1247G>A) is classified Conflicting classifications of pathogenicity in ENTREP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-26). AlphaMissense: likely benign (0.0721); Rare (popmax 0.171%, afr).

How common is ENTREP1 p.Arg416Gln (c.1247G>A) in the general population?

ENTREP1 p.Arg416Gln (c.1247G>A) is rare (popmax 0.171%, afr) (gnomAD).

What do computational predictors say about ENTREP1 p.Arg416Gln (c.1247G>A)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

ENTREP1 p.Arg416Gln

c.1247G>A · rs150027118 · VCV1317819

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.171%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.52	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 0.36	GERP -0.73, phastCons 0.006
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.71 · regional, not allelic
Overall
CADD	17.88	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R263Q vs ClinVar R416Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.171% African / African-American · 127/74,408 alleles

Filtering AF 0.147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.0112% 181/1,611,820 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.171%	586
Remaining individualsnot grpmax-eligible	0.0144%	6,939
Admixed American	0.00837%	11,942
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,789
South Asian	0.0033%	30,276
European (non-Finnish)	0.00297%	33,698

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.Arg416Gln
Coding: c.1247G>A
MANE Select: NM_001347995
dbSNP: rs150027118
Type: single nucleotide variant
Location: chr9:69385879 (GRCh38)
Structure: AlphaFold pLDDT 60.47
Residue 416: the 'mediates interaction with epn1' region

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

Similar variants

ENTREP1 p.Arg416Trp Uncertain significance ★ ⚠ 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-arg416gln (accessed [today's date]).

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