Is EN1 p.Ala15Pro (c.43G>C) pathogenic?

EN1 p.Ala15Pro (c.43G>C) is classified Uncertain significance in EN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely benign (0.1211); Rare (popmax 0.157%, mid).

How common is EN1 p.Ala15Pro (c.43G>C) in the general population?

EN1 p.Ala15Pro (c.43G>C) is rare (popmax 0.157%, mid) (gnomAD).

What do computational predictors say about EN1 p.Ala15Pro (c.43G>C)?

AlphaMissense predicts likely benign (score 0.1211) — an in-silico prediction, not a clinical call.

EN1 p.Ala15Pro

c.43G>C · rs767769043 · VCV2353906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1211 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.157%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1211	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -5.32	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 2.6	GERP 0.58, phastCons 0.054
Regional constraint	o/e 1.06	unconstrained · MANE · 810 bp · p 0.2 · regional, not allelic
Overall
CADD	20.4	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 0.157% Middle Eastern · 6/3,830 alleles

Filtering AF 0.0682% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0483%

Overall 0.0207% 277/1,335,370 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.157%	638
Admixed American	0.0781%	1,281
European (non-Finnish)	0.0225%	4,444
Remaining individualsnot grpmax-eligible	0.0137%	7,292
South Asian	0.0085%	11,767
Finnishnot grpmax-eligible	0.00237%	42,242
African / African-American	0.00154%	65,130

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: EN1
Protein: p.Ala15Pro
Coding: c.43G>C
MANE Select: NM_001426
dbSNP: rs767769043
Type: single nucleotide variant
Location: chr2:118847125 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 58.76
Residue 15: the 'disordered' region

Full EN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EN1 p.Ala201= Likely benign ★★ same type
EN1 p.Pro76= Likely benign ★★ same type
EN1 p.Ala132Thr Uncertain significance ★ ⚠ same type
EN1 p.Ala150Val Uncertain significance ★ ⚠ same type
EN1 p.Ala151Ser Uncertain significance ★ ⚠ same type
EN1 p.Ala190Val Uncertain significance ★ ⚠ same type
EN1 p.Ala192Val Uncertain significance ★ ⚠ same type
EN1 p.Ala195Ser 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/en1-p-ala15pro (accessed [today's date]).

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