Is KCNE5 p.Pro45= (c.135T>C) pathogenic?

KCNE5 p.Pro45= (c.135T>C) is classified Likely benign in KCNE5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-05). Ultra-rare (popmax 0.0272%, mid); Associated with Brugada syndrome.

What condition is associated with KCNE5 p.Pro45= (c.135T>C)?

KCNE5 p.Pro45= (c.135T>C) is associated with Brugada syndrome (ClinVar).

How common is KCNE5 p.Pro45= (c.135T>C) in the general population?

KCNE5 p.Pro45= (c.135T>C) is ultra-rare (popmax 0.0272%, mid) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

KCNE5 p.Pro45=

c.135T>C · rs748919636 · VCV2912439

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0272%, mid)

Conditions

Brugada syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP -0.73, phastCons 0.99
Overall
CADD	9.216	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0272% Middle Eastern · 1/3,677 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00264% 32/1,209,872 alleles · ultra-rare exomes 28/1,096,763 · genomes 4/113,109 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0272%	3,677
European (non-Finnish)	0.00335%	29,842
African / African-American	0.00174%	57,587

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: KCNE5
Protein: p.Pro45=
Coding: c.135T>C
MANE Select: NM_012282
dbSNP: rs748919636
Type: single nucleotide variant
Location: chrX:109624886 (GRCh38)
Structure: AlphaFold pLDDT 64.43

Full KCNE5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Brugada syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

KCNE5 p.Asp112Glu Uncertain significance ★★ ⚠ same condition
KCNE5 p.Gln120Ter Uncertain significance ★★ same condition
KCNE5 p.Gln7Arg Uncertain significance ★★ ⚠ same condition
KCNE5 p.Gln96Glu Uncertain significance ★★ ⚠ same condition
KCNE5 p.Glu100Gln Uncertain significance ★★ ⚠ same condition
KCNE5 p.Glu102Ala Uncertain significance ★★ ⚠ same condition
KCNE5 p.Glu102Lys Uncertain significance ★★ ⚠ same condition
KCNE5 p.Glu19Gln Uncertain significance ★★ ⚠ same condition

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/kcne5-p-pro45 (accessed [today's date]).

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