Is EDN3 p.Pro89Ser (c.265C>T) pathogenic?

EDN3 p.Pro89Ser (c.265C>T) is classified Uncertain significance in EDN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely benign (0.0888); Ultra-rare (popmax 0.0173%, afr).

How common is EDN3 p.Pro89Ser (c.265C>T) in the general population?

EDN3 p.Pro89Ser (c.265C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about EDN3 p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

EDN3 p.Pro89Ser

c.265C>T · VCV4680886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.08	GERP -1.9
Regional constraint	o/e 1.06	unconstrained · MANE · 24 kb · p 0.32 · regional, not allelic
Overall
CADD	13.84	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 0.0173% African / African-American · 13/75,050 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.0013% 21/1,614,104 alleles · ultra-rare exomes 13/1,461,816 · genomes 8/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,773
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.005%	20,009

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.Pro89Ser
Coding: c.265C>T
MANE Select: NM_207034
Type: single nucleotide variant
Location: chr20:59301622 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 56.84 · 1 PDB
Residue 89: the 'disordered' region

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

Similar variants

EDN3 c.-19C>A Uncertain significance ★★ same type
EDN3 c.-86G>A Uncertain significance ★★ same type
EDN3 p.Arg137Gln Uncertain significance ★★ same type
EDN3 p.Arg154Gln Uncertain significance ★★ ⚠ same type
EDN3 p.Arg158Ser Uncertain significance ★★ ⚠ same type
EDN3 p.Arg230Cys Uncertain significance ★★ ⚠ same type
EDN3 p.Arg230His Uncertain significance ★★ ⚠ same type
EDN3 p.Arg230Pro Uncertain significance ★★ ⚠ same type

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-pro89ser (accessed [today's date]).

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