Is EN2 p.Gly58Asp (c.173G>A) pathogenic?

EN2 p.Gly58Asp (c.173G>A) is classified Uncertain significance in EN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: ambiguous (0.5459); Very rare (popmax 0.00231%, nfe).

How common is EN2 p.Gly58Asp (c.173G>A) in the general population?

EN2 p.Gly58Asp (c.173G>A) is very rare (popmax 0.00231%, nfe) (gnomAD).

What do computational predictors say about EN2 p.Gly58Asp (c.173G>A)?

AlphaMissense predicts ambiguous (score 0.5459) — an in-silico prediction, not a clinical call.

EN2 p.Gly58Asp

c.173G>A · VCV4017923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5459	ambiguous
REVEL	0.379	indeterminate
SaProt	LLR -7.70	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 4,306 bp · p 0.32 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00231% European (non-Finnish) · 25/1,080,582 alleles

Filtering AF 0.00159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00183% 26/1,417,012 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00231%	43,223
South Asian	0.00166%	60,172

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.Gly58Asp
Coding: c.173G>A
MANE Select: NM_001427
Type: single nucleotide variant
Location: chr7:155458550 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI 0.39 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 62.51

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

Similar variants

EN2 p.Gly58Ser 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
EN2 p.Ala297Thr 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-gly58asp (accessed [today's date]).

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