Is EDN3 p.Pro229Ser (c.685C>T) pathogenic?

EDN3 p.Pro229Ser (c.685C>T) is classified Uncertain significance in EDN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.0825); Ultra-rare (popmax 0.02%, amr); Associated with Hirschsprung disease, susceptibility to, 4.

What condition is associated with EDN3 p.Pro229Ser (c.685C>T)?

EDN3 p.Pro229Ser (c.685C>T) is associated with Hirschsprung disease, susceptibility to, 4 (ClinVar).

How common is EDN3 p.Pro229Ser (c.685C>T) in the general population?

EDN3 p.Pro229Ser (c.685C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about EDN3 p.Pro229Ser (c.685C>T)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

EDN3 p.Pro229Ser

c.685C>T · rs757559436 · VCV897567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hirschsprung disease, susceptibility to, 4

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.94	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	GERP -3.6, phastCons 0.001
Regional constraint	o/e 1.06	unconstrained · MANE · 24 kb · p 0.32 · regional, not allelic
Overall
CADD	8.691	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 0.02% Admixed American · 12/59,998 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000867% 14/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,000
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,908

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.Pro229Ser
Coding: c.685C>T
MANE Select: NM_207034
dbSNP: rs757559436
Type: single nucleotide variant
Location: chr20:59324427 (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

Similar variants

EDN3 p.Pro229= Likely benign ★ 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-pro229ser (accessed [today's date]).

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