Is RYR2 p.Val4522= (c.13566C>T) pathogenic?

RYR2 p.Val4522= (c.13566C>T) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.15%, afr); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Val4522= (c.13566C>T)?

RYR2 p.Val4522= (c.13566C>T) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Val4522= (c.13566C>T) in the general population?

RYR2 p.Val4522= (c.13566C>T) is low-frequency (popmax 1.15%, afr) (gnomAD).

RYR2 p.Val4522=

c.13566C>T · rs57360419 · VCV43727

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.15%, afr)

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 2.3	GERP 1.1, phastCons 1
Overall
CADD	11.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.15% African / African-American · 854/74,526 alleles

Filtering AF 1.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.0663% 1,053/1,588,656 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.15%	87
Admixed American	0.116%	860
Middle Eastern	0.0994%	1,006
Remaining individualsnot grpmax-eligible	0.0842%	1,187
European (non-Finnish)	0.00643%	15,554
South Asian	0.00115%	87,306

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.Val4522=
Coding: c.13566C>T
MANE Select: NM_001035
dbSNP: rs57360419
Type: single nucleotide variant
Location: chr1:237792107 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4522: 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

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.Arg169Leu 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-val4522 (accessed [today's date]).

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