Is RYR2 p.Ser451= (c.1353C>T) pathogenic?

RYR2 p.Ser451= (c.1353C>T) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0165%, sas); Associated with catecholaminergic polymorphic ventricular tachycardia.

What condition is associated with RYR2 p.Ser451= (c.1353C>T)?

RYR2 p.Ser451= (c.1353C>T) is associated with catecholaminergic polymorphic ventricular tachycardia, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Ser451= (c.1353C>T) in the general population?

RYR2 p.Ser451= (c.1353C>T) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

RYR2 p.Ser451=

Q: How is Catecholaminergic polymorphic ventricular tachycardia inherited?

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

c.1353C>T · rs764245031 · VCV681759

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Conditions

catecholaminergic polymorphic ventricular tachycardia

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 -10	GERP -3.6
Overall
CADD	0.142	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/91,056 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00285% 46/1,613,400 alleles · ultra-rare exomes 44/1,461,296 · genomes 2/152,104 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,070
Middle Eastern	0.0164%	6,080
East Asian	0.00669%	14,953
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
European (non-Finnish)	0.0022%	45,371

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.Ser451=
Coding: c.1353C>T
MANE Select: NM_001035
dbSNP: rs764245031
Type: single nucleotide variant
Location: chr1:237454451 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 451: an α-helix

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

Disease context

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

Also linked: cardiomyopathy catecholaminergic polymorphic ventricular tachycardia 1

For Catecholaminergic polymorphic ventricular tachycardia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

RYR2 p.Ser451Cys 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
RYR2 p.Arg169Gln 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-ser451 (accessed [today's date]).

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