Is RYR2 p.Leu2129Pro (c.6386T>C) pathogenic?

RYR2 p.Leu2129Pro (c.6386T>C) is classified Uncertain significance in RYR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 8.48e-05%, nfe); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with RYR2 p.Leu2129Pro (c.6386T>C)?

RYR2 p.Leu2129Pro (c.6386T>C) is associated with catecholaminergic polymorphic ventricular tachycardia 1, cardiomyopathy (ClinVar).

How common is RYR2 p.Leu2129Pro (c.6386T>C) in the general population?

RYR2 p.Leu2129Pro (c.6386T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RYR2 p.Leu2129Pro (c.6386T>C)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

RYR2 p.Leu2129Pro

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.6386T>C · rs1260384416 · VCV1753196

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic · top 1% in RYR2
REVEL	0.976	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 11 kb · p 1.5e-16 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,898 alleles

Overall 6.2e-05% 1/1,613,842 alleles · very rare exomes 0/1,461,680 · genomes 1/152,162 · 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.Leu2129Pro
Coding: c.6386T>C
MANE Select: NM_001035
dbSNP: rs1260384416
Type: single nucleotide variant
Location: chr1:237628026 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2129: the '4 x approximate repeats' region; 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: cardiomyopathy

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

RYR2 p.Leu2129= Likely benign ★ 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-leu2129pro (accessed [today's date]).

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