Is RYR2 p.Pro1565= (c.4695T>C) pathogenic?

RYR2 p.Pro1565= (c.4695T>C) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-10). Rare (popmax 0.245%, eas); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Pro1565= (c.4695T>C)?

RYR2 p.Pro1565= (c.4695T>C) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Pro1565= (c.4695T>C) in the general population?

RYR2 p.Pro1565= (c.4695T>C) is rare (popmax 0.245%, eas) (gnomAD).

RYR2 p.Pro1565=

c.4695T>C · rs368826662 · VCV296725

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.245%, eas)

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 -1	GERP -4, phastCons 0.004
Overall
CADD	6.393	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.245% East Asian · 109/44,546 alleles

Filtering AF 0.207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.193%

Overall 0.00717% 115/1,604,364 alleles · rare exomes 105/1,452,096 · genomes 10/152,268 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.245%	409
Remaining individualsnot grpmax-eligible	0.00966%	10,349

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.Pro1565=
Coding: c.4695T>C
MANE Select: NM_001035
dbSNP: rs368826662
Type: single nucleotide variant
Location: chr1:237610773 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1565: the '4 x approximate repeats' region; a β-strand

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.Pro1565Ala Conflicting classifications of pathogenicity ★ ⚠ 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-pro1565 (accessed [today's date]).

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