Is RYR2 p.Ser453= (c.1359C>T) pathogenic?

RYR2 p.Ser453= (c.1359C>T) is classified Benign in RYR2 (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-04). Common (popmax 77%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Ser453= (c.1359C>T)?

RYR2 p.Ser453= (c.1359C>T) is associated with Cardiovascular phenotype, cardiomyopathy, cardiac rhythm disease (ClinVar).

RYR2 p.Ser453=

Q: How common is RYR2 p.Ser453= (c.1359C>T) in the general population?

RYR2 p.Ser453= (c.1359C>T) is common (popmax 77%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1359C>T · rs3765097 · VCV43728

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

gnomAD v4.1

Common

common (popmax 77%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

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 -0.62	GERP -3.6, phastCons 0.034
Overall
CADD	2.379	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 77% East Asian · 34,502/44,830 alleles

Filtering AF 76.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 76%

Overall 59.3% 957,259/1,613,098 alleles · common exomes 877,907/1,461,152 · genomes 79,352/151,946 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	77%	1
Amishnot grpmax-eligible	62.6%	2
European (non-Finnish)	60.9%	2
Finnishnot grpmax-eligible	59.3%	2
Ashkenazi Jewishnot grpmax-eligible	59.3%	2
Remaining individualsnot grpmax-eligible	58.3%	2
Admixed American	58.3%	2
South Asian	55.5%	2
Middle Eastern	48.6%	2
African / African-American	31.5%	3

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.Ser453=
Coding: c.1359C>T
MANE Select: NM_001035
dbSNP: rs3765097
Type: single nucleotide variant
Location: chr1:237454457 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 453: an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy cardiac rhythm disease catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia

Similar variants

RYR2 p.Ser453Thr Uncertain significance ★★ same residue
RYR2 p.Ser453Cys 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-ser453 (accessed [today's date]).

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