Is EN2 p.Arg130Gln (c.389G>A) pathogenic?

EN2 p.Arg130Gln (c.389G>A) is classified Uncertain significance in EN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0794); Very rare (popmax 0.00644%, nfe).

How common is EN2 p.Arg130Gln (c.389G>A) in the general population?

EN2 p.Arg130Gln (c.389G>A) is very rare (popmax 0.00644%, nfe) (gnomAD).

What do computational predictors say about EN2 p.Arg130Gln (c.389G>A)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

EN2 p.Arg130Gln

c.389G>A · VCV4664256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00644%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -6.06	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 6.9	GERP 7.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 4,306 bp · p 0.32 · regional, not allelic
Overall
CADD	22.6	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 0.00644% European (non-Finnish) · 69/1,070,636 alleles

Filtering AF 0.00518% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00475%

Overall 0.00525% 72/1,371,178 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00644%	15,516
Remaining individualsnot grpmax-eligible	0.00382%	26,178
African / African-American	0.00154%	64,996

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: EN2
Protein: p.Arg130Gln
Coding: c.389G>A
MANE Select: NM_001427
Type: single nucleotide variant
Location: chr7:155458766 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI 0.39 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 62.51
Residue 130: the 'disordered' region

Full EN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EN2 p.Arg130Gly Uncertain significance ★ ⚠ same residue
EN2 p.Arg130Trp Uncertain significance ★ ⚠ same residue
EN2 p.Asn68Ser Uncertain significance ★★ ⚠ same type
EN2 p.Leu318= Benign ★★ same type
EN2 p.Ser200= Benign ★★ same type
EN2 p.Ala109Val Uncertain significance ★ ⚠ same type
EN2 p.Ala167Ser Uncertain significance ★ ⚠ same type
EN2 p.Ala183Thr 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/en2-p-arg130gln (accessed [today's date]).

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