Is EN1 p.Pro66Leu (c.197C>T) pathogenic?

EN1 p.Pro66Leu (c.197C>T) is classified Uncertain significance in EN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-23). AlphaMissense: likely benign (0.1658); Very rare (popmax 0.00616%, eas).

How common is EN1 p.Pro66Leu (c.197C>T) in the general population?

EN1 p.Pro66Leu (c.197C>T) is very rare (popmax 0.00616%, eas) (gnomAD).

What do computational predictors say about EN1 p.Pro66Leu (c.197C>T)?

AlphaMissense predicts likely benign (score 0.1658) — an in-silico prediction, not a clinical call.

EN1 p.Pro66Leu

c.197C>T · rs1186108250 · VCV2603565

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00616%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1658	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -6.77	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 5	GERP -1.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 810 bp · p 0.2 · regional, not allelic
Overall
CADD	18.89	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 0.00616% East Asian · 2/32,472 alleles

Filtering AF 0.00102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000381%

Overall 0.000362% 5/1,381,416 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00616%	16,236
European (non-Finnish)	0.000278%	359,132

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.Pro66Leu
Coding: c.197C>T
MANE Select: NM_001426
dbSNP: rs1186108250
Type: single nucleotide variant
Location: chr2:118846971 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 58.76
Residue 66: 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.Ala15Pro Uncertain significance ★ ⚠ same type
EN1 p.Ala190Val Uncertain significance ★ ⚠ same type
EN1 p.Ala192Val 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-pro66leu (accessed [today's date]).

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