Is EDN2 p.Arg90His (c.269G>A) pathogenic?

EDN2 p.Arg90His (c.269G>A) is classified Uncertain significance in EDN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.3492); Ultra-rare (popmax 0.0192%, sas).

How common is EDN2 p.Arg90His (c.269G>A) in the general population?

EDN2 p.Arg90His (c.269G>A) is ultra-rare (popmax 0.0192%, sas) (gnomAD).

What do computational predictors say about EDN2 p.Arg90His (c.269G>A)?

AlphaMissense predicts ambiguous (score 0.3492) — an in-silico prediction, not a clinical call.

EDN2 p.Arg90His

c.269G>A · VCV4016234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3492 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0192%, sas)

Computational evidence

Protein change
AlphaMissense	0.3492	ambiguous
REVEL	0.503	indeterminate
SaProt	LLR -10.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,189 bp · p 0.26 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0192% South Asian · 17/88,450 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.00259% 41/1,585,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0192%	5,203
Middle Eastern	0.0168%	5,952
East Asian	0.00716%	13,965
Remaining individualsnot grpmax-eligible	0.00652%	15,328
African / African-American	0.00413%	24,203
Admixed American	0.00182%	54,946
European (non-Finnish)	0.00103%	97,372

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: EDN2
Protein: p.Arg90His
Coding: c.269G>A
MANE Select: NM_001956
Type: single nucleotide variant
Location: chr1:41482541 (GRCh38)
Gene constraint: LOEUF 0.969 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.58

Full EDN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDN2 c.345-4G>A Benign ★★ same type
EDN2 p.Ala105Thr Uncertain significance ★ ⚠ same type
EDN2 p.Ala26Pro Uncertain significance ★ ⚠ same type
EDN2 p.Ala39Gly Uncertain significance ★ ⚠ same type
EDN2 p.Ala39Val Uncertain significance ★ ⚠ same type
EDN2 p.Arg102Lys Uncertain significance ★ ⚠ same type
EDN2 p.Arg124Gln Uncertain significance ★ ⚠ same type
EDN2 p.Arg124Trp 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/edn2-p-arg90his (accessed [today's date]).

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