RYR1 p.Pro4491=
c.13473A>C · rs770239842 · VCV544471
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00224%, eas)
Conditions
1
malignant hyperthermia, susceptibility to, 1
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 -20 | GERP -3.5 |
| Overall | ||
| CADD | 0.151 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00224%
East Asian · 1/44,658 alleles
Filtering AF
8e-05%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 5.4e-05%
Overall
0.000373%
6/1,606,748 alleles · very rare
exomes 4/1,454,584 · genomes 2/152,164 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.00224% | 44,658 |
| African / African-American | 0.00134% | 74,854 |
| European (non-Finnish) | 0.00034% | 294,241 |
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.Pro4491=
- Coding
- c.13473A>C
- MANE Select
- NM_000540
- dbSNP
- rs770239842
- Type
- single nucleotide variant
- Location
- chr19:38566946 (GRCh38)
- Gene constraint
- LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Residue 4491
- the 'disordered' region
Similar variants
- RYR1 p.Pro4491Ala Uncertain significance ★★ ⚠ same residue
- RYR1 p.Pro4491Thr Uncertain significance ★★ ⚠ 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
- RYR1 c.9472+1G>A Pathogenic ★★★ same condition
- RYR1 p.Ala152Asp 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/ryr1-p-pro4491 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown