Is EDNRB p.Ser65Pro (c.193T>C) pathogenic?

EDNRB p.Ser65Pro (c.193T>C) is classified Uncertain significance in EDNRB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.0622); Very rare (popmax 8.51e-05%, nfe).

How common is EDNRB p.Ser65Pro (c.193T>C) in the general population?

EDNRB p.Ser65Pro (c.193T>C) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about EDNRB p.Ser65Pro (c.193T>C)?

AlphaMissense predicts likely benign (score 0.0622) — an in-silico prediction, not a clinical call.

EDNRB p.Ser65Pro

c.193T>C · rs2501609675 · VCV2849307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0622	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -6.15	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 3.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 20 kb · p 8.1e-06 · regional, not allelic
Overall
CADD	14.96	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 8.51e-05% European (non-Finnish) · 1/1,174,400 alleles

Overall 6.23e-05% 1/1,605,640 alleles · very rare exomes 1/1,453,586 · genomes 0/152,054 · joint denominator

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: EDNRB
Protein: p.Ser65Pro
Coding: c.193T>C
MANE Select: NM_001122659
dbSNP: rs2501609675
Type: single nucleotide variant
Location: chr13:77918381 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.49 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 75.37 · 18 PDB

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

Similar variants

EDNRB p.Ser65Ter Pathogenic ★ same residue
EDNRB c.1085+1G>A Likely pathogenic ★★ same type
EDNRB c.596+1G>A Pathogenic/Likely pathogenic ★★ same type
EDNRB c.802-1G>A Likely pathogenic ★★ same type
EDNRB p.Arg253Ter Pathogenic ★★ same type
EDNRB c.*1412C>T Uncertain significance ★★ same type
EDNRB p.Ala310Thr Uncertain significance ★★ same type
EDNRB p.Arg124Lys 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/ednrb-p-ser65pro (accessed [today's date]).

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