Is EN1 p.Ala216Ser (c.646G>T) pathogenic?

EN1 p.Ala216Ser (c.646G>T) is classified Uncertain significance in EN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.0963); Very rare (popmax 0.0002%, nfe).

How common is EN1 p.Ala216Ser (c.646G>T) in the general population?

EN1 p.Ala216Ser (c.646G>T) is very rare (popmax 0.0002%, nfe) (gnomAD).

What do computational predictors say about EN1 p.Ala216Ser (c.646G>T)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

EN1 p.Ala216Ser

c.646G>T · VCV4664241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0002%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.48, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 810 bp · p 0.2 · regional, not allelic
Overall
CADD	17.48	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 0.0002% European (non-Finnish) · 2/998,592 alleles

Filtering AF 3.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.3e-05%

Overall 0.00018% 2/1,113,982 alleles · very rare

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.Ala216Ser
Coding: c.646G>T
MANE Select: NM_001426
Type: single nucleotide variant
Location: chr2:118846522 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 58.76

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-ala216ser (accessed [today's date]).

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