Is EDN3 p.Asp190fs (c.568_569del) pathogenic?

EDN3 p.Asp190fs (c.568569del) is classified Conflicting classifications of pathogenicity in EDN3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-26). Ultra-rare (popmax 0.0593%, sas); Associated with Waardenburg syndrome type 4B.

What condition is associated with EDN3 p.Asp190fs (c.568_569del)?

EDN3 p.Asp190fs (c.568_569del) is associated with Waardenburg syndrome type 4B (ClinVar).

How common is EDN3 p.Asp190fs (c.568_569del) in the general population?

EDN3 p.Asp190fs (c.568_569del) is ultra-rare (popmax 0.0593%, sas) (gnomAD).

How is Waardenburg-Shah syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EDN3 p.Asp190fs

c.568_569del · VCV4083438

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0593%, sas)

Conditions

Waardenburg syndrome type 4B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (4 of 5, 21 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.5	GERP 1.3
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0593% South Asian · 54/91,072 alleles

Filtering AF 0.0466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0421%

Overall 0.00564% 91/1,614,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0593%	1,687
Remaining individualsnot grpmax-eligible	0.0144%	6,944
European (non-Finnish)	0.00229%	43,703
Finnishnot grpmax-eligible	0.00156%	64,030

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.Asp190fs
Coding: c.568_569del
MANE Select: NM_207034
Type: Deletion
Location: chr20:59322396 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 56.84 · 1 PDB
Residue 190: the 'disordered' region

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

Disease context

Waardenburg syndrome type 4B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Waardenburg-Shah syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal

Similar variants

EDN3 p.48ETVAGPGE[3] Uncertain significance ★★ same condition
EDN3 p.Arg230Cys Uncertain significance ★★ ⚠ same condition
EDN3 p.Ser15Ala Uncertain significance ★★ ⚠ same condition
EDN3 p.Ala142= Benign/Likely benign ★★ same condition
EDN3 p.Ala224Thr Likely benign ★★ same condition
EDN3 p.Thr189fs Benign/Likely benign ★★ same condition
EDN3 p.His112Asn Likely pathogenic ★ same condition
EDN3 p.Arg158Cys Uncertain significance ★ ⚠ 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-asp190fs (accessed [today's date]).

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