Is EDN3 p.Pro217= (c.651C>T) pathogenic?

EDN3 p.Pro217= (c.651C>T) is classified Uncertain significance in EDN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0646%, eas); Associated with Hirschsprung disease, susceptibility to, 4.

What condition is associated with EDN3 p.Pro217= (c.651C>T)?

EDN3 p.Pro217= (c.651C>T) is associated with Hirschsprung disease, susceptibility to, 4 (ClinVar).

How common is EDN3 p.Pro217= (c.651C>T) in the general population?

EDN3 p.Pro217= (c.651C>T) is ultra-rare (popmax 0.0646%, eas) (gnomAD).

EDN3 p.Pro217=

c.651C>T · rs748005608 · VCV897566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0646%, 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 -2.5	GERP -2.5
Overall
CADD	5.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0646% East Asian · 29/44,902 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0399%

Overall 0.00601% 97/1,614,016 alleles · ultra-rare exomes 92/1,461,874 · genomes 5/152,142 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0646%	1,548
Admixed American	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00449%	22,265
African / African-American	0.00401%	24,966
South Asian	0.00329%	30,357

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.Pro217=
Coding: c.651C>T
MANE Select: NM_207034
dbSNP: rs748005608
Type: single nucleotide variant
Location: chr20:59324393 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 56.84 · 1 PDB
Residue 217: the 'disordered' region

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 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
EDN3 c.*146C>T 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-pro217 (accessed [today's date]).

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