RYR2 p.Val663=
c.1989C>G · rs2545834964 · VCV2774256
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.000763%, nfe)
Conditions
2
cardiomyopathy
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.21 | acceptor loss, 3 bp away · masked 0 · deltas |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 2.8 | GERP 0.12, phastCons 1 |
| Overall | ||
| CADD | 8.462 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.000763%
European (non-Finnish) · 9/1,179,868 alleles
Filtering AF
0.000359%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00026%
Overall
0.000558%
9/1,613,946 alleles · very rare
exomes 9/1,461,660 · genomes 0/152,286 · 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.Val663=
- Coding
- c.1989C>G
- MANE Select
- NM_001035
- dbSNP
- rs2545834964
- Type
- single nucleotide variant
- Location
- chr1:237496538 (GRCh38)
- Gene constraint
- LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Residue 663
- the b30.2/spry 1 domain
Similar variants
- RYR2 p.Val663Ala Uncertain significance ★★ same residue
- RYR2 p.Val663Ile Conflicting classifications of pathogenicity ★ ⚠ 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-val663 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown