Is RYR2 p.Arg15= (c.43C>A) pathogenic?

RYR2 p.Arg15= (c.43C>A) is classified Likely benign in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-20). Very rare (popmax 0.00307%, eas); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with RYR2 p.Arg15= (c.43C>A)?

RYR2 p.Arg15= (c.43C>A) is associated with catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Arg15= (c.43C>A) in the general population?

RYR2 p.Arg15= (c.43C>A) is very rare (popmax 0.00307%, eas) (gnomAD).

RYR2 p.Arg15=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.43C>A · rs868468826 · VCV2729312

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00307%, eas)

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

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 3.2	GERP -0.03, phastCons 1
Overall
CADD	11.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00307% East Asian · 1/32,612 alleles

Overall 7.93e-05% 1/1,261,798 alleles · very rare exomes 1/1,109,614 · genomes 0/152,184 · 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: RYR2
Protein: p.Arg15=
Coding: c.43C>A
MANE Select: NM_001035
dbSNP: rs868468826
Type: single nucleotide variant
Location: chr1:237042564 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 15: a β-strand

Full RYR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

catecholaminergic polymorphic ventricular tachycardia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

RYR2 p.Arg15Pro Likely pathogenic ★ same residue
RYR2 p.Arg15_Thr16insVal Uncertain significance ★ same residue
RYR2 p.Ala2387Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala2387Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala391Asp Likely pathogenic ★★ same condition
RYR2 p.Ala4091Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala4510Pro Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala77Val Pathogenic/Likely pathogenic ★★ 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/ryr2-p-arg15 (accessed [today's date]).

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