Is EDNRA p.Phe260= (c.780C>T) pathogenic?

EDNRA p.Phe260= (c.780C>T) is classified Likely benign in EDNRA (ClinVar, Single submitter, 2 submitters; last evaluated 2023-11-04). Ultra-rare (popmax 0.017%, nfe).

How common is EDNRA p.Phe260= (c.780C>T) in the general population?

EDNRA p.Phe260= (c.780C>T) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

EDNRA p.Phe260=

c.780C>T · rs150937673 · VCV1988796

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP -12	GERP -5.2
Overall
CADD	0.918	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.017% European (non-Finnish) · 201/1,179,458 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0137% 221/1,612,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,680
European (non-Finnish)grpmax	0.017%	5,868
African / African-American	0.00669%	14,943
Admixed American	0.00334%	29,932
East Asian	0.00223%	44,800
South Asian	0.0011%	90,960

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe260=
Coding: c.780C>T
MANE Select: NM_001957
dbSNP: rs150937673
Type: single nucleotide variant
Location: chr4:147535909 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.45 · 5 PDB
Residue 260: an α-helix

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-phe260 (accessed [today's date]).

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