RYR1 p.Pro4495=
c.13485G>A · rs554451286 · VCV1542307
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0392%, sas)
Conditions
2
RYR1-related disorder
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -2.5 | GERP -2.3, phastCons 0.16 |
| Overall | ||
| CADD | 1.073 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0392%
South Asian · 35/89,198 alleles
Filtering AF
0.0289%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0254%
Overall
0.00436%
70/1,604,944 alleles · ultra-rare
exomes 62/1,452,682 · genomes 8/152,262 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0392% | 2,549 |
| African / African-American | 0.00534% | 18,734 |
| Remaining individualsnot grpmax-eligible | 0.00322% | 31,053 |
| European (non-Finnish) | 0.00238% | 41,996 |
| East Asian | 0.00224% | 44,582 |
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
- RYR1
- Protein
- p.Pro4495=
- Coding
- c.13485G>A
- MANE Select
- NM_000540
- dbSNP
- rs554451286
- Type
- single nucleotide variant
- Location
- chr19:38566958 (GRCh38)
- Gene constraint
- LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Residue 4495
- the 'disordered' region
Similar variants
- RYR1 p.Pro4495Arg Uncertain significance ★★ ⚠ same residue
- RYR1 p.Pro4495Leu Uncertain significance ★★ ⚠ same residue
- RYR1 p.Pro4495Ser Uncertain significance ★★ ⚠ same residue
- RYR1 p.Pro4495Gln Likely benign ★ same residue
- RYR1 c.10347+1G>A Pathogenic ★★★ same condition
- RYR1 c.10348-6C>G Pathogenic ★★★ same condition
- RYR1 c.1925+1G>C Likely pathogenic ★★★ same condition
- RYR1 c.8310+1G>T 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/ryr1-p-pro4495 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown