Is EN2 p.Ser29Leu (c.86C>T) pathogenic?

EN2 p.Ser29Leu (c.86C>T) is classified Uncertain significance in EN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.13); Very rare (popmax 0.00674%, nfe).

How common is EN2 p.Ser29Leu (c.86C>T) in the general population?

EN2 p.Ser29Leu (c.86C>T) is very rare (popmax 0.00674%, nfe) (gnomAD).

What do computational predictors say about EN2 p.Ser29Leu (c.86C>T)?

AlphaMissense predicts likely benign (score 0.13) — an in-silico prediction, not a clinical call.

EN2 p.Ser29Leu

c.86C>T · VCV4017920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.13 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00674%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.13	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -9.24	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 1.1	GERP 2.8, phastCons 0.11
Regional constraint	o/e 1.04	unconstrained · MANE · 4,306 bp · p 0.32 · regional, not allelic
Overall
CADD	14.81	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 0.00674% European (non-Finnish) · 69/1,023,962 alleles

Filtering AF 0.00542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00496%

Overall 0.00561% 73/1,300,734 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0108%	9,268
European (non-Finnish)grpmax	0.00674%	14,840
Remaining individualsnot grpmax-eligible	0.00207%	48,422
African / African-American	0.00155%	64,418

Ashkenazi Jewish 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: EN2
Protein: p.Ser29Leu
Coding: c.86C>T
MANE Select: NM_001427
Type: single nucleotide variant
Location: chr7:155458463 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI 0.39 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 62.51
Residue 29: the 'disordered' region

Full EN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EN2 p.Asn68Ser Uncertain significance ★★ ⚠ same type
EN2 p.Leu318= Benign ★★ same type
EN2 p.Ser200= Benign ★★ same type
EN2 p.Ala109Val Uncertain significance ★ ⚠ same type
EN2 p.Ala167Ser Uncertain significance ★ ⚠ same type
EN2 p.Ala183Thr Uncertain significance ★ ⚠ same type
EN2 p.Ala297Thr Uncertain significance ★ ⚠ same type
EN2 p.Ala40Glu 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/en2-p-ser29leu (accessed [today's date]).

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