Is RYR2 p.Pro4439Ser (c.13315C>T) pathogenic?

RYR2 p.Pro4439Ser (c.13315C>T) is classified Uncertain significance in RYR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-06). AlphaMissense: likely benign (0.1152); Absent from gnomAD v4.1; Associated with catecholaminergic polymorphic ventricular tachycardia.

What condition is associated with RYR2 p.Pro4439Ser (c.13315C>T)?

RYR2 p.Pro4439Ser (c.13315C>T) is associated with catecholaminergic polymorphic ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Pro4439Ser (c.13315C>T) in the general population?

RYR2 p.Pro4439Ser (c.13315C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR2 p.Pro4439Ser (c.13315C>T)?

AlphaMissense predicts likely benign (score 0.1152) — an in-silico prediction, not a clinical call.

RYR2 p.Pro4439Ser

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.13315C>T · rs746608828 · VCV1993017

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1152 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

catecholaminergic polymorphic ventricular tachycardia

Computational evidence

Protein change
AlphaMissense	0.1152	likely benign
REVEL	0.473	indeterminate
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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 7,920 bp · p 0.00018 · regional, not allelic
Overall
CADD	24.1	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.Pro4439Ser
Coding: c.13315C>T
MANE Select: NM_001035
dbSNP: rs746608828
Type: single nucleotide variant
Location: chr1:237786023 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4439: the 'disordered' region

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: 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.Pro4439Arg Uncertain significance ★★ same residue
RYR2 p.Pro4439Thr 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-pro4439ser (accessed [today's date]).

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