Is RYR2 p.Ser134= (c.402C>T) pathogenic?

RYR2 p.Ser134= (c.402C>T) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-27). Ultra-rare (popmax 0.0384%, amr); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Ser134= (c.402C>T)?

RYR2 p.Ser134= (c.402C>T) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Ser134= (c.402C>T) in the general population?

RYR2 p.Ser134= (c.402C>T) is ultra-rare (popmax 0.0384%, amr) (gnomAD).

RYR2 p.Ser134=

c.402C>T · rs776832019 · VCV919149

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, amr)

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 0.018	GERP -1.2, phastCons 0.79
Overall
CADD	7.833	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0384% Admixed American · 23/59,830 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.0018% 29/1,612,592 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0384%	2,601
Remaining individualsnot grpmax-eligible	0.00481%	20,801
African / African-American	0.00134%	74,890
European (non-Finnish)	0.00017%	589,671

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.Ser134=
Coding: c.402C>T
MANE Select: NM_001035
dbSNP: rs776832019
Type: single nucleotide variant
Location: chr1:237374734 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 134: the mir 1 domain

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 catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia

Similar variants

RYR2 p.Ser134Cys Uncertain significance ★★ ⚠ same residue
RYR2 p.Ser134Pro 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-ser134 (accessed [today's date]).

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