Is EDN2 p.Val4Met (c.10G>A) pathogenic?

EDN2 p.Val4Met (c.10G>A) is classified Likely benign in EDN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0866); Rare (popmax 0.35%, eas).

How common is EDN2 p.Val4Met (c.10G>A) in the general population?

EDN2 p.Val4Met (c.10G>A) is rare (popmax 0.35%, eas) (gnomAD).

What do computational predictors say about EDN2 p.Val4Met (c.10G>A)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

EDN2 p.Val4Met

c.10G>A · VCV4246626

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.35%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -8.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -2.9
Regional constraint	o/e 0.93	unconstrained · MANE · 5,189 bp · p 0.26 · regional, not allelic
Overall
CADD	0.059	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 0.35% East Asian · 145/41,380 alleles

Filtering AF 0.304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.286%

Overall 0.0115% 180/1,560,020 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.35%	285
Remaining individualsnot grpmax-eligible	0.0298%	3,361
Middle Eastern	0.0167%	5,996
South Asian	0.00829%	12,061
Ashkenazi Jewishnot grpmax-eligible	0.00348%	28,742
Admixed American	0.00192%	52,106
European (non-Finnish)	0.000608%	164,585

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.Val4Met
Coding: c.10G>A
MANE Select: NM_001956
Type: single nucleotide variant
Location: chr1:41484592 (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-val4met (accessed [today's date]).

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