Is EDNRB p.Phe397Val (c.1189T>G) pathogenic?

EDNRB p.Phe397Val (c.1189T>G) is classified Uncertain significance in EDNRB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.9817); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with EDNRB p.Phe397Val (c.1189T>G)?

EDNRB p.Phe397Val (c.1189T>G) is associated with Inborn genetic diseases (ClinVar).

How common is EDNRB p.Phe397Val (c.1189T>G) in the general population?

EDNRB p.Phe397Val (c.1189T>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EDNRB p.Phe397Val (c.1189T>G)?

AlphaMissense predicts likely pathogenic (score 0.9817) — an in-silico prediction, not a clinical call.

EDNRB p.Phe397Val

c.1189T>G · VCV4246641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9817	likely pathogenic
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -12.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 20 kb · p 8.1e-06 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/59,790 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000497% 8/1,610,992 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,790
European (non-Finnish)	0.000594%	168,312

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.Phe397Val
Coding: c.1189T>G
MANE Select: NM_001122659
Type: single nucleotide variant
Location: chr13:77899864 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.49 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 75.37 · 18 PDB
Residue 397: a UniProt-annotated variant site (found in patients with waardenburg syndrome 2; likely pathogenic; loss of cell membrane location; new cytoplasmic location); an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EDNRB p.Phe397Tyr Uncertain significance ★ ⚠ same residue
EDNRB p.Arg124Lys Uncertain significance ★★ ⚠ same condition
EDNRB p.Arg83Cys Uncertain significance ★★ ⚠ same condition
EDNRB p.Asp274Gly Uncertain significance ★★ ⚠ same condition
EDNRB p.Asp34Glu Uncertain significance ★★ ⚠ same condition
EDNRB p.Cys380Ser Uncertain significance ★★ ⚠ same condition
EDNRB p.Gly429Arg Uncertain significance ★★ ⚠ same condition
EDNRB p.Ile180Met 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-phe397val (accessed [today's date]).

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