Is EN1 p.Ser221Trp (c.662C>G) pathogenic?

EN1 p.Ser221Trp (c.662C>G) is classified Uncertain significance in EN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.4018); Very rare (popmax 0.00263%, eas).

How common is EN1 p.Ser221Trp (c.662C>G) in the general population?

EN1 p.Ser221Trp (c.662C>G) is very rare (popmax 0.00263%, eas) (gnomAD).

What do computational predictors say about EN1 p.Ser221Trp (c.662C>G)?

AlphaMissense predicts ambiguous (score 0.4018) — an in-silico prediction, not a clinical call.

EN1 p.Ser221Trp

c.662C>G · VCV4248906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, eas)

Computational evidence

Protein change
AlphaMissense	0.4018	ambiguous
REVEL	0.391	indeterminate
SaProt	LLR -9.14	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 810 bp · p 0.2 · regional, not allelic
Overall
CADD	25.8	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 0.00263% East Asian · 1/37,986 alleles

Overall 0.000218% 3/1,378,378 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00263%	37,986
Remaining individualsnot grpmax-eligible	0.0017%	58,792
European (non-Finnish)	8.77e-05%	1,139,684

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.Ser221Trp
Coding: c.662C>G
MANE Select: NM_001426
Type: single nucleotide variant
Location: chr2:118846506 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 58.76
Residue 221: the 'disordered' region

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

Similar variants

EN1 p.Ser221Thr Uncertain significance ★ ⚠ same residue
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

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-ser221trp (accessed [today's date]).

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