Is EDNRA p.Ser46Arg (c.136A>C) pathogenic?

EDNRA p.Ser46Arg (c.136A>C) is classified Uncertain significance in EDNRA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: likely benign (0.1309); Very rare (popmax 0.000847%, nfe).

How common is EDNRA p.Ser46Arg (c.136A>C) in the general population?

EDNRA p.Ser46Arg (c.136A>C) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about EDNRA p.Ser46Arg (c.136A>C)?

AlphaMissense predicts likely benign (score 0.1309) — an in-silico prediction, not a clinical call.

EDNRA p.Ser46Arg

c.136A>C · VCV4777931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1309 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1309	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -7.95	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 2.1	GERP -1.1, phastCons 0.99
Regional constraint	o/e 0.73	unconstrained · MANE · 307 bp · p 0.003 · regional, not allelic
Overall
CADD	15.39	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 0.000847% European (non-Finnish) · 10/1,180,032 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,130 alleles · very rare

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: EDNRA
Protein: p.Ser46Arg
Coding: c.136A>C
MANE Select: NM_001957
Type: single nucleotide variant
Location: chr4:147485817 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.45 · 5 PDB

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

Similar variants

EDNRA p.Gly354Ser Uncertain significance ★★ ⚠ same type
EDNRA p.His33Arg Uncertain significance ★★ ⚠ same type
EDNRA p.Ile405Val Uncertain significance ★★ ⚠ same type
EDNRA p.Ile82Leu Uncertain significance ★★ ⚠ same type
EDNRA p.Val155Ile Uncertain significance ★★ ⚠ same type
EDNRA c.1034+19G>A Benign/Likely benign ★★ same type
EDNRA c.1034+52T>C Benign ★★ same type
EDNRA c.1035-151G>A Benign ★★ 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/ednra-p-ser46arg (accessed [today's date]).

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