RYR1 p.Pro978=
c.2934G>A · rs746139608 · VCV2917559
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00334%, amr)
Conditions
1
RYR1-related disorder
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 -14 | GERP -3.7 |
| Overall | ||
| CADD | 0.035 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00334%
Admixed American · 2/59,960 alleles
Filtering AF
0.000875%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000443%
Overall
0.000682%
11/1,613,230 alleles · very rare
exomes 10/1,461,056 · genomes 1/152,174 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00334% | 29,980 |
| South Asian | 0.0033% | 30,342 |
| East Asian | 0.00223% | 44,866 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,430 |
| European (non-Finnish) | 0.000339% | 294,971 |
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.Pro978=
- Coding
- c.2934G>A
- MANE Select
- NM_000540
- dbSNP
- rs746139608
- Type
- single nucleotide variant
- Location
- chr19:38466154 (GRCh38)
- Gene constraint
- LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Residue 978
- the '6 x approximate repeats' region
Similar variants
- RYR1 p.Pro978Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
- RYR1 p.Pro978Ser Uncertain significance ★ ⚠ same residue
- RYR1 c.10627-1G>C Pathogenic/Likely pathogenic ★★ same condition
- RYR1 c.14647-1G>C Likely pathogenic ★★ same condition
- RYR1 c.14869-1G>T Pathogenic/Likely pathogenic ★★ same condition
- RYR1 c.2683-1G>A Pathogenic/Likely pathogenic ★★ same condition
- RYR1 c.2870+1G>A Pathogenic/Likely pathogenic ★★ same condition
- RYR1 c.3381+1G>A 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-pro978 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown