Is RYR2 p.Leu433Pro (c.1298T>C) pathogenic?

RYR2 p.Leu433Pro (c.1298T>C) is classified Pathogenic in RYR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2017-12-26). AlphaMissense: likely pathogenic (0.9911); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Leu433Pro (c.1298T>C)?

RYR2 p.Leu433Pro (c.1298T>C) is associated with Cardiovascular phenotype, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Leu433Pro (c.1298T>C) in the general population?

RYR2 p.Leu433Pro (c.1298T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR2 p.Leu433Pro (c.1298T>C)?

AlphaMissense predicts likely pathogenic (score 0.9911) — an in-silico prediction, not a clinical call.

RYR2 p.Leu433Pro

c.1298T>C · rs121918602 · VCV12959

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9911 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9911	likely pathogenic ✓ concordant with ClinVar · top 8% in RYR2
REVEL	0.756	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 194 kb · p 7.7e-10 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RYR2
Protein: p.Leu433Pro
Coding: c.1298T>C
MANE Select: NM_001035
dbSNP: rs121918602
Type: single nucleotide variant
Location: chr1:237454396 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 433: an α-helix; a UniProt-annotated variant site (in cpvt1)

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: long QT syndrome catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia

Similar variants

RYR2 p.Leu433Phe 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
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-leu433pro (accessed [today's date]).

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