Is RYR2 p.Ser134Pro (c.400T>C) pathogenic?

RYR2 p.Ser134Pro (c.400T>C) is classified Uncertain significance in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: ambiguous (0.473); Absent from gnomAD v4.1; Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with RYR2 p.Ser134Pro (c.400T>C)?

RYR2 p.Ser134Pro (c.400T>C) is associated with catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Ser134Pro (c.400T>C) in the general population?

RYR2 p.Ser134Pro (c.400T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR2 p.Ser134Pro (c.400T>C)?

AlphaMissense predicts ambiguous (score 0.473) — an in-silico prediction, not a clinical call.

RYR2 p.Ser134Pro

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.400T>C · rs2529939909 · VCV1972731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.473 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.473	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP 1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 335 kb · p 0.00039 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RYR2
Protein: p.Ser134Pro
Coding: c.400T>C
MANE Select: NM_001035
dbSNP: rs2529939909
Type: single nucleotide variant
Location: chr1:237374732 (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

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.Ser134Cys Uncertain significance ★★ ⚠ same residue
RYR2 p.Ser134= Benign/Likely benign ★★ 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-ser134pro (accessed [today's date]).

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