RYR2 p.Phe48Ser
c.143T>C · rs774559907 · VCV1411252
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6461 | likely pathogenic |
|---|---|---|
| REVEL | 0.863 | moderately pathogenic-leaning |
| SaProt | — | not scored · why |
| ⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 6.1 | GERP 2.2, phastCons 1 |
| Regional constraint | o/e 0.75 | unconstrained · MANE · 335 kb · p 0.00039 · regional, not allelic |
| Overall | ||
| CADD | 22.6 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.0137% | 7,277 |
| Remaining individualsnot grpmax-eligible | 0.00324% | 30,879 |
| European (non-Finnish)grpmax | 8.56e-05% | 1,168,470 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Phe48Ser
- Coding
- c.143T>C
- MANE Select
- NM_001035
- dbSNP
- rs774559907
- Type
- single nucleotide variant
- Location
- chr1:237270591 (GRCh38)
- Gene constraint
- LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Residue 48
- a β-strand
Disease context
catecholaminergic polymorphic ventricular tachycardia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: cardiomyopathy
For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- No data available
Similar variants
- 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
- RYR2 p.Arg176Gln 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-phe48ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown