Is EN2 p.Asn68Ser (c.203A>G) pathogenic?

EN2 p.Asn68Ser (c.203A>G) is classified Uncertain significance in EN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-18). AlphaMissense: likely pathogenic (0.6042); Very rare (popmax 0.0023%, amr).

How common is EN2 p.Asn68Ser (c.203A>G) in the general population?

EN2 p.Asn68Ser (c.203A>G) is very rare (popmax 0.0023%, amr) (gnomAD).

What do computational predictors say about EN2 p.Asn68Ser (c.203A>G)?

AlphaMissense predicts likely pathogenic (score 0.6042) — an in-silico prediction, not a clinical call.

EN2 p.Asn68Ser

c.203A>G · rs1307196217 · VCV2275040

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6042	likely pathogenic
REVEL	0.306	indeterminate
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 4.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 4,306 bp · p 0.32 · regional, not allelic
Overall
CADD	23.3	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 0.0023% Admixed American · 1/43,560 alleles

Filtering AF 0.000853% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00069%

Overall 0.00115% 17/1,475,682 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0023%	43,560
European (non-Finnish)	0.00144%	69,416

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.Asn68Ser
Coding: c.203A>G
MANE Select: NM_001427
dbSNP: rs1307196217
Type: single nucleotide variant
Location: chr7:155458580 (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.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
EN2 p.Ala40Glu Uncertain significance ★ ⚠ same type
EN2 p.Ala40Gly 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-asn68ser (accessed [today's date]).

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