RYR2 p.Pro1535=
c.4605G>A · rs201916326 · VCV43787
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 15 submitters
gnomAD v4.1
Rare
low-frequency (popmax 1.47%, sas)
Conditions
3
cardiomyopathy
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.061 | GERP -4, phastCons 0.049 |
| Overall | ||
| CADD | 8.658 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.47%
South Asian · 1,328/90,620 alleles
Filtering AF
1.4%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.37%
Overall
0.206%
3,325/1,611,458 alleles · low-frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 1.47% | 68 |
| Ashkenazi Jewishnot grpmax-eligible | 1.44% | 70 |
| Middle Eastern | 0.843% | 119 |
| Remaining individualsnot grpmax-eligible | 0.29% | 345 |
| European (non-Finnish) | 0.109% | 914 |
| Admixed American | 0.0568% | 1,760 |
| African / African-American | 0.0147% | 6,815 |
| Finnishnot grpmax-eligible | 0.00782% | 12,788 |
| East Asian | 0.00224% | 44,690 |
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.Pro1535=
- Coding
- c.4605G>A
- MANE Select
- NM_001035
- dbSNP
- rs201916326
- Type
- single nucleotide variant
- Location
- chr1:237602033 (GRCh38)
- Gene constraint
- LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Residue 1535
- the b30.2/spry 3 domain; the '4 x approximate repeats' region
Similar variants
- RYR2 p.Pro1535Leu Uncertain significance ★★ same residue
- RYR2 p.Pro1535Gln Uncertain significance ★ same residue
- RYR2 p.Pro1535Ser 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
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-pro1535 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown