Is RYR2 p.Pro3312= (c.9936T>A) pathogenic?

RYR2 p.Pro3312= (c.9936T>A) is classified Likely benign in RYR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-29). Very rare (popmax 0.00892%, eas); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with RYR2 p.Pro3312= (c.9936T>A)?

RYR2 p.Pro3312= (c.9936T>A) is associated with catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia (ClinVar).

How common is RYR2 p.Pro3312= (c.9936T>A) in the general population?

RYR2 p.Pro3312= (c.9936T>A) is very rare (popmax 0.00892%, eas) (gnomAD).

RYR2 p.Pro3312=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.9936T>A · rs967337973 · VCV1111473

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

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 -0.35	GERP 0.94, phastCons 0.25
Overall
CADD	7.726	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,850 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,611,444 alleles · very rare exomes 4/1,459,158 · genomes 0/152,286 · 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.Pro3312=
Coding: c.9936T>A
MANE Select: NM_001035
dbSNP: rs967337973
Type: single nucleotide variant
Location: chr1:237708892 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 3312: an α-helix

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

Also linked: catecholaminergic polymorphic ventricular tachycardia

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

RYR2 p.Pro3312Thr 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
RYR2 p.Arg169Gln 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-pro3312 (accessed [today's date]).

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