Is RYR1 p.Pro50= (c.150C>G) pathogenic?

RYR1 p.Pro50= (c.150C>G) is classified Likely benign in RYR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-11). Ultra-rare (popmax 0.015%, amr); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Pro50= (c.150C>G)?

RYR1 p.Pro50= (c.150C>G) is associated with RYR1-related disorder, malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro50= (c.150C>G) in the general population?

RYR1 p.Pro50= (c.150C>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

RYR1 p.Pro50=

c.150C>G · rs554528443 · VCV478204

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Conditions

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 0.96	GERP -2.7, phastCons 1
Overall
CADD	10.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/59,816 alleles

Filtering AF 0.00775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0058%

Overall 0.000558% 9/1,611,950 alleles · ultra-rare exomes 6/1,459,668 · genomes 3/152,282 · joint denominator

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.Pro50=
Coding: c.150C>G
MANE Select: NM_000540
dbSNP: rs554528443
Type: single nucleotide variant
Location: chr19:38440849 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full RYR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: malignant hyperthermia, susceptibility to, 1

Similar variants

RYR1 p.Pro50His 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
RYR1 p.Ala2200Val 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-pro50 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown