Is EDN3 p.Ala142= (c.426G>A) pathogenic?

EDN3 p.Ala142= (c.426G>A) is classified Benign/Likely benign in EDN3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-23). Rare (popmax 0.59%, eas); Associated with Hirschsprung disease, susceptibility to, 4.

What condition is associated with EDN3 p.Ala142= (c.426G>A)?

EDN3 p.Ala142= (c.426G>A) is associated with Hirschsprung disease, susceptibility to, 4, Waardenburg syndrome type 4B (ClinVar).

How common is EDN3 p.Ala142= (c.426G>A) in the general population?

EDN3 p.Ala142= (c.426G>A) is rare (popmax 0.59%, eas) (gnomAD).

EDN3 p.Ala142=

c.426G>A · rs187049336 · VCV339124

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.59%, eas)

Conditions

Hirschsprung disease, susceptibility to, 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -3.9
Overall
CADD	1.466	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.59% East Asian · 265/44,882 alleles

Filtering AF 0.532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.509%

Overall 0.0355% 573/1,614,220 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.59%	169
South Asian	0.203%	492
Remaining individualsnot grpmax-eligible	0.0912%	1,097
Middle Eastern	0.033%	3,031
Admixed American	0.0117%	8,576
European (non-Finnish)	0.00475%	21,072
Finnishnot grpmax-eligible	0.00156%	64,042

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: EDN3
Protein: p.Ala142=
Coding: c.426G>A
MANE Select: NM_207034
dbSNP: rs187049336
Type: single nucleotide variant
Location: chr20:59321077 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 56.84 · 1 PDB

Full EDN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hirschsprung disease, susceptibility to, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Waardenburg syndrome type 4B

Similar variants

EDN3 p.Ala142Val Uncertain significance ★ ⚠ same residue
EDN3 c.-86G>A Uncertain significance ★★ same condition
EDN3 p.Arg230Cys Uncertain significance ★★ ⚠ same condition
EDN3 p.Arg230His Uncertain significance ★★ ⚠ same condition
EDN3 p.Leu208Ser Uncertain significance ★★ ⚠ same condition
EDN3 p.Ser15Ala Uncertain significance ★★ ⚠ same condition
EDN3 c.-44C>T Likely benign ★★ same condition
EDN3 c.-77T>A Benign ★★ same condition

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/edn3-p-ala142 (accessed [today's date]).

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