Is RYR2 p.Pro4596= (c.13788A>T) pathogenic?

RYR2 p.Pro4596= (c.13788A>T) is classified Likely benign in RYR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-08). Very rare (popmax 0.00017%, nfe); Associated with catecholaminergic polymorphic ventricular tachycardia.

What condition is associated with RYR2 p.Pro4596= (c.13788A>T)?

RYR2 p.Pro4596= (c.13788A>T) is associated with catecholaminergic polymorphic ventricular tachycardia, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Pro4596= (c.13788A>T) in the general population?

RYR2 p.Pro4596= (c.13788A>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

RYR2 p.Pro4596=

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.13788A>T · rs368675632 · VCV515138

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

catecholaminergic polymorphic ventricular tachycardia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -4.3
Overall
CADD	1.572	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,173,524 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,606,244 alleles · very rare exomes 1/1,454,262 · genomes 1/151,982 · joint denominator

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.Pro4596=
Coding: c.13788A>T
MANE Select: NM_001035
dbSNP: rs368675632
Type: single nucleotide variant
Location: chr1:237793872 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4596: 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.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
RYR2 p.Arg176Gln 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-pro4596 (accessed [today's date]).

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