Is EDN2 p.Arg95His (c.284G>A) pathogenic?

EDN2 p.Arg95His (c.284G>A) is classified Uncertain significance in EDN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-23). AlphaMissense: ambiguous (0.488); Very rare (popmax 0.00175%, amr).

How common is EDN2 p.Arg95His (c.284G>A) in the general population?

EDN2 p.Arg95His (c.284G>A) is very rare (popmax 0.00175%, amr) (gnomAD).

What do computational predictors say about EDN2 p.Arg95His (c.284G>A)?

AlphaMissense predicts ambiguous (score 0.488) — an in-silico prediction, not a clinical call.

EDN2 p.Arg95His

c.284G>A · VCV3843434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.488	ambiguous
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -7.12	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,189 bp · p 0.26 · regional, not allelic
Overall
CADD	29.8	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 0.00175% Admixed American · 1/57,184 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000314% 5/1,594,114 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00175%	57,184
European (non-Finnish)	0.000341%	292,934

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.Arg95His
Coding: c.284G>A
MANE Select: NM_001956
Type: single nucleotide variant
Location: chr1:41482526 (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-arg95his (accessed [today's date]).

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