Is EDNRB p.Ser413= (c.1239C>G) pathogenic?

EDNRB p.Ser413= (c.1239C>G) is classified Conflicting classifications of pathogenicity in EDNRB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-20). Rare (popmax 0.91%, mid); Associated with Hirschsprung disease, susceptibility to, 2.

What condition is associated with EDNRB p.Ser413= (c.1239C>G)?

EDNRB p.Ser413= (c.1239C>G) is associated with Hirschsprung disease, susceptibility to, 2 (ClinVar).

How common is EDNRB p.Ser413= (c.1239C>G) in the general population?

EDNRB p.Ser413= (c.1239C>G) is rare (popmax 0.91%, mid) (gnomAD).

EDNRB p.Ser413=

c.1239C>G · rs139317762 · VCV255140

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.91%, mid)

Conditions

Hirschsprung disease, susceptibility to, 2

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 4.6	GERP 0.5, phastCons 1
Overall
CADD	7.899	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.91% Middle Eastern · 55/6,044 alleles

Filtering AF 0.718% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.649%

Overall 0.189% 3,047/1,612,108 alleles · rare exomes 2,779/1,460,098 · genomes 268/152,010 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.91%	110
Ashkenazi Jewishnot grpmax-eligible	0.742%	135
Remaining individualsnot grpmax-eligible	0.273%	367
European (non-Finnish)	0.199%	503
Admixed American	0.182%	549
Amishnot grpmax-eligible	0.11%	912
South Asian	0.102%	979
African / African-American	0.0641%	1,561
Finnishnot grpmax-eligible	0.0125%	7,992

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: EDNRB
Protein: p.Ser413=
Coding: c.1239C>G
MANE Select: NM_001122659
dbSNP: rs139317762
Type: single nucleotide variant
Location: chr13:77898290 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.49 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 75.37 · 18 PDB
Residue 413: a UniProt-annotated variant site (found in patients with waardenburg syndrome 2; likely pathogenic; loss of cell membrane location; new cytoplasmic location)

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

Disease context

Hirschsprung disease, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EDNRB c.596+1G>A Pathogenic/Likely pathogenic ★★ same condition
EDNRB c.*1412C>T Uncertain significance ★★ same condition
EDNRB p.Arg64Leu Uncertain significance ★★ ⚠ same condition
EDNRB p.Asn353Lys Uncertain significance ★★ ⚠ same condition
EDNRB p.Cys131Arg Uncertain significance ★★ ⚠ same condition
EDNRB p.Cys380Ser Uncertain significance ★★ ⚠ same condition
EDNRB p.Gly429Arg Uncertain significance ★★ ⚠ same condition
EDNRB p.Ser419Leu 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/ednrb-p-ser413 (accessed [today's date]).

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