Is RYR1 p.Pro3208= (c.9624G>A) pathogenic?

RYR1 p.Pro3208= (c.9624G>A) is classified Likely benign in RYR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-09). Very rare (popmax 0.00272%, afr); Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with RYR1 p.Pro3208= (c.9624G>A)?

RYR1 p.Pro3208= (c.9624G>A) is associated with malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro3208= (c.9624G>A) in the general population?

RYR1 p.Pro3208= (c.9624G>A) is very rare (popmax 0.00272%, afr) (gnomAD).

RYR1 p.Pro3208=

c.9624G>A · rs552470353 · VCV1566500

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

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 -5.8	GERP -4.9
Overall
CADD	0.202	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00272% African / African-American · 2/73,450 alleles

Filtering AF 0.000452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.00045% 7/1,557,258 alleles · very rare exomes 6/1,405,038 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00272%	36,725
Admixed American	0.00193%	51,784
South Asian	0.00118%	84,402
European (non-Finnish)	0.000261%	383,514

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.Pro3208=
Coding: c.9624G>A
MANE Select: NM_000540
dbSNP: rs552470353
Type: single nucleotide variant
Location: chr19:38516156 (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

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

Similar variants

RYR1 p.Pro3208Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro3208 (accessed [today's date]).

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