Is RYR1 p.Arg3287Cys (c.9859C>T) pathogenic?

RYR1 p.Arg3287Cys (c.9859C>T) is classified Conflicting classifications of pathogenicity in RYR1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-01-30). AlphaMissense: likely benign (0.2691); Ultra-rare (popmax 0.0602%, eas); Associated with central core myopathy.

What condition is associated with RYR1 p.Arg3287Cys (c.9859C>T)?

RYR1 p.Arg3287Cys (c.9859C>T) is associated with central core myopathy, malignant hyperthermia, susceptibility to, 1, congenital fiber-type disproportion myopathy (ClinVar).

How common is RYR1 p.Arg3287Cys (c.9859C>T) in the general population?

RYR1 p.Arg3287Cys (c.9859C>T) is ultra-rare (popmax 0.0602%, eas) (gnomAD).

How is Central core disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RYR1 p.Arg3287Cys (c.9859C>T)?

AlphaMissense predicts likely benign (score 0.2691) — an in-silico prediction, not a clinical call.

RYR1 p.Arg3287Cys

c.9859C>T · rs201276068 · VCV544426

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2691 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0602%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

central core myopathy

Computational evidence

Protein change
AlphaMissense	0.2691	likely benign
REVEL	0.857	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 39 kb · p 7.8e-08 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0602% East Asian · 27/44,872 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.0044% 71/1,613,886 alleles · ultra-rare exomes 64/1,461,642 · genomes 7/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0602%	1,662
Middle Eastern	0.0165%	6,062
South Asian	0.00439%	22,770
European (non-Finnish)	0.00322%	31,050
Admixed American	0.00167%	60,006

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.Arg3287Cys
Coding: c.9859C>T
MANE Select: NM_000540
dbSNP: rs201276068
Type: single nucleotide variant
Location: chr19:38517532 (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

central core myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: malignant hyperthermia, susceptibility to, 1 congenital fiber-type disproportion myopathy congenital multicore myopathy with external ophthalmoplegia King-Denborough syndrome

For Central core disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

RYR1 p.Arg3287His Uncertain significance ★★ ⚠ same residue
RYR1 p.Arg3287= Likely benign ★★ 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-arg3287cys (accessed [today's date]).

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