Is EN2 p.Pro63Leu (c.188C>T) pathogenic?

EN2 p.Pro63Leu (c.188C>T) is classified Uncertain significance in EN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely benign (0.3059); Very rare (popmax 0.0014%, sas).

How common is EN2 p.Pro63Leu (c.188C>T) in the general population?

EN2 p.Pro63Leu (c.188C>T) is very rare (popmax 0.0014%, sas) (gnomAD).

What do computational predictors say about EN2 p.Pro63Leu (c.188C>T)?

AlphaMissense predicts likely benign (score 0.3059) — an in-silico prediction, not a clinical call.

EN2 p.Pro63Leu

c.188C>T · VCV4664248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0014%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3059	likely benign
REVEL	0.358	indeterminate
SaProt	LLR -7.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 3.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 4,306 bp · p 0.32 · regional, not allelic
Overall
CADD	24.5	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 0.0014% South Asian · 1/71,348 alleles

Filtering AF 0.000383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000682% 10/1,465,860 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0014%	71,348
European (non-Finnish)	0.000814%	122,885

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.Pro63Leu
Coding: c.188C>T
MANE Select: NM_001427
Type: single nucleotide variant
Location: chr7:155458565 (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.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
EN2 p.Ala40Glu 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-pro63leu (accessed [today's date]).

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