Is RYR1 p.Pro4493= (c.13479C>T) pathogenic?

RYR1 p.Pro4493= (c.13479C>T) is classified Likely benign in RYR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-19). Ultra-rare (popmax 0.0166%, mid); Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with RYR1 p.Pro4493= (c.13479C>T)?

RYR1 p.Pro4493= (c.13479C>T) is associated with malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro4493= (c.13479C>T) in the general population?

RYR1 p.Pro4493= (c.13479C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

RYR1 p.Pro4493=

c.13479C>T · rs768885593 · VCV1594383

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

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 -2.1
Overall
CADD	0.003	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,026 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000905%

Overall 0.000934% 15/1,605,628 alleles · ultra-rare exomes 15/1,453,456 · genomes 0/152,172 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,026
South Asian	0.00448%	22,325
European (non-Finnish)	0.00085%	117,644

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.Pro4493=
Coding: c.13479C>T
MANE Select: NM_000540
dbSNP: rs768885593
Type: single nucleotide variant
Location: chr19:38566952 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4493: a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

malignant hyperthermia, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RYR1 p.Pro4493Ser Uncertain significance ★★ ⚠ same residue
RYR1 p.Pro4493Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
RYR1 p.Pro4493His 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

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-pro4493 (accessed [today's date]).

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