Is RYR2 p.Pro1124= (c.3372G>A) pathogenic?

RYR2 p.Pro1124= (c.3372G>A) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-23). Very rare (popmax 0.00833%, amr); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Pro1124= (c.3372G>A)?

RYR2 p.Pro1124= (c.3372G>A) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Pro1124= (c.3372G>A) in the general population?

RYR2 p.Pro1124= (c.3372G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

RYR2 p.Pro1124=

c.3372G>A · rs368017980 · VCV138942

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 -20	GERP -3.6
Overall
CADD	0.124	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/59,996 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00576% 93/1,613,848 alleles · very rare exomes 88/1,461,680 · genomes 5/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	11,999
Remaining individualsnot grpmax-eligible	0.008%	12,493
European (non-Finnish)	0.00661%	15,127
Finnishnot grpmax-eligible	0.00469%	21,339
South Asian	0.0022%	45,539

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.Pro1124=
Coding: c.3372G>A
MANE Select: NM_001035
dbSNP: rs368017980
Type: single nucleotide variant
Location: chr1:237566724 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1124: the b30.2/spry 2 domain; 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.Pro1124Gln Uncertain significance ★★ same residue
RYR2 p.Pro1124Leu Conflicting classifications of pathogenicity ★ same residue
RYR2 p.Pro1124Ser 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-pro1124 (accessed [today's date]).

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