Is RYR2 p.Leu730Phe (c.2188C>T) pathogenic?

RYR2 p.Leu730Phe (c.2188C>T) is classified Uncertain significance in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-02). AlphaMissense: likely pathogenic (0.5669); Very rare (popmax 0.00667%, amr); Associated with catecholaminergic polymorphic ventricular tachycardia.

What condition is associated with RYR2 p.Leu730Phe (c.2188C>T)?

RYR2 p.Leu730Phe (c.2188C>T) is associated with catecholaminergic polymorphic ventricular tachycardia (ClinVar).

How common is RYR2 p.Leu730Phe (c.2188C>T) in the general population?

RYR2 p.Leu730Phe (c.2188C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about RYR2 p.Leu730Phe (c.2188C>T)?

AlphaMissense predicts likely pathogenic (score 0.5669) — an in-silico prediction, not a clinical call.

RYR2 p.Leu730Phe

Q: How is Catecholaminergic polymorphic ventricular tachycardia inherited?

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

c.2188C>T · rs766829251 · VCV3071577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

catecholaminergic polymorphic ventricular tachycardia

Computational evidence

Protein change
AlphaMissense	0.5669	likely pathogenic
REVEL	0.441	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 194 kb · p 7.7e-10 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,613,688 alleles · very rare exomes 5/1,461,454 · genomes 0/152,234 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
European (non-Finnish)	8.48e-05%	1,179,714

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.Leu730Phe
Coding: c.2188C>T
MANE Select: NM_001035
dbSNP: rs766829251
Type: single nucleotide variant
Location: chr1:237496737 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 730: the b30.2/spry 1 domain; a β-strand

Full RYR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

catecholaminergic polymorphic ventricular tachycardia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Catecholaminergic polymorphic ventricular tachycardia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

RYR2 p.Leu730= Likely benign ★★ same residue
RYR2 p.Ala2387Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg169Gln Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg420Trp Pathogenic ★★ same condition
RYR2 p.Ile4867Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Leu433Pro Pathogenic ★★ same condition
RYR2 p.Tyr4725Cys Pathogenic/Likely pathogenic ★★ same condition
RYR2 c.10494+1G>T Uncertain significance ★★ 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-leu730phe (accessed [today's date]).

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