Is RYR2 p.Val1024Ile (c.3070G>A) pathogenic?

RYR2 p.Val1024Ile (c.3070G>A) is classified Uncertain significance in RYR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0742); Very rare (popmax 0.0067%, eas); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with RYR2 p.Val1024Ile (c.3070G>A)?

RYR2 p.Val1024Ile (c.3070G>A) is associated with catecholaminergic polymorphic ventricular tachycardia 1, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia (ClinVar).

How common is RYR2 p.Val1024Ile (c.3070G>A) in the general population?

RYR2 p.Val1024Ile (c.3070G>A) is very rare (popmax 0.0067%, eas) (gnomAD).

What do computational predictors say about RYR2 p.Val1024Ile (c.3070G>A)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

RYR2 p.Val1024Ile

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.3070G>A · rs1291873158 · VCV922927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.381	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 8.2	GERP -0.007, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 194 kb · p 7.7e-10 · regional, not allelic
Overall
CADD	23.1	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 0.0067% East Asian · 3/44,746 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000893%

Overall 0.000746% 12/1,608,788 alleles · very rare exomes 12/1,456,774 · genomes 0/152,014 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0067%	14,915
African / African-American	0.00267%	37,443
European (non-Finnish)	0.000594%	168,236

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.Val1024Ile
Coding: c.3070G>A
MANE Select: NM_001035
dbSNP: rs1291873158
Type: single nucleotide variant
Location: chr1:237550547 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1024: the '4 x approximate repeats' region; a turn

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 catecholaminergic polymorphic ventricular tachycardia

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

RYR2 p.Val1024Leu Conflicting classifications of pathogenicity ★ same residue
RYR2 p.Val1024= 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

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-val1024ile (accessed [today's date]).

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