Is EN1 p.Ala201= (c.603G>C) pathogenic?

EN1 p.Ala201= (c.603G>C) is classified Likely benign in EN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-21). Rare (popmax 0.747%, amr).

How common is EN1 p.Ala201= (c.603G>C) in the general population?

EN1 p.Ala201= (c.603G>C) is rare (popmax 0.747%, amr) (gnomAD).

EN1 p.Ala201=

c.603G>C · VCV3388064

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.747%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	9.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.747% Admixed American · 168/22,496 alleles

Filtering AF 0.655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.619%

Overall 0.529% 6,398/1,209,590 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.07%	20
Admixed Americangrpmax	0.747%	134
Ashkenazi Jewishnot grpmax-eligible	0.663%	151
European (non-Finnish)	0.588%	170
Remaining individualsnot grpmax-eligible	0.548%	182
African / African-American	0.0843%	1,186
Finnishnot grpmax-eligible	0.0832%	1,202
South Asian	0.0658%	1,520
Middle Eastern	0.0327%	3,056

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala201=
Coding: c.603G>C
MANE Select: NM_001426
Type: single nucleotide variant
Location: chr2:118846565 (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.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
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-ala201 (accessed [today's date]).

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