Is RYR2 p.Arg276= (c.828A>G) pathogenic?

RYR2 p.Arg276= (c.828A>G) is classified Conflicting classifications of pathogenicity in RYR2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-28). Rare (popmax 0.242%, afr); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with RYR2 p.Arg276= (c.828A>G)?

RYR2 p.Arg276= (c.828A>G) is associated with catecholaminergic polymorphic ventricular tachycardia 1, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia (ClinVar).

How common is RYR2 p.Arg276= (c.828A>G) in the general population?

RYR2 p.Arg276= (c.828A>G) is rare (popmax 0.242%, afr) (gnomAD).

RYR2 p.Arg276=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.828A>G · rs180711819 · VCV296705

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.242%, afr)

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 0.34	GERP 0.56, phastCons 0.47
Overall
CADD	8.171	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.242% African / African-American · 181/74,916 alleles

Filtering AF 0.213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.202%

Overall 0.0178% 288/1,613,478 alleles · rare exomes 162/1,461,488 · genomes 126/151,990 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.242%	414
Middle Eastern	0.0825%	1,212
Admixed American	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.0288%	3,470
European (non-Finnish)	0.00526%	19,027
South Asian	0.0011%	91,062

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.Arg276=
Coding: c.828A>G
MANE Select: NM_001035
dbSNP: rs180711819
Type: single nucleotide variant
Location: chr1:237417103 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 276: the mir 3 domain; 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

Also linked: cardiomyopathy catecholaminergic polymorphic ventricular tachycardia

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

RYR2 p.Arg276Gly Uncertain significance ★ ⚠ same residue
RYR2 p.Arg276Lys 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-arg276 (accessed [today's date]).

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