Is RYR2 p.Pro3209= (c.9627G>A) pathogenic?

RYR2 p.Pro3209= (c.9627G>A) is classified Likely benign in RYR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-20). Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Pro3209= (c.9627G>A)?

RYR2 p.Pro3209= (c.9627G>A) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Pro3209= (c.9627G>A) in the general population?

RYR2 p.Pro3209= (c.9627G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

RYR2 p.Pro3209=

c.9627G>A · rs377730320 · VCV926261

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Cardiovascular phenotype

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 -14	GERP -4.3
Overall
CADD	0.058	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,884 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00031% 5/1,613,710 alleles · very rare exomes 3/1,461,602 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,442
East Asian	0.00223%	44,886
South Asian	0.0011%	91,084
European (non-Finnish)	8.48e-05%	1,179,806

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.Pro3209=
Coding: c.9627G>A
MANE Select: NM_001035
dbSNP: rs377730320
Type: single nucleotide variant
Location: chr1:237706995 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)

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.Pro3209Leu Uncertain significance ★★ same residue
RYR2 p.Pro3209Ser Uncertain significance ★★ same residue
RYR2 p.Pro3209Thr 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

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-pro3209 (accessed [today's date]).

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