Is RYR1 p.Cys603Arg (c.1807T>C) pathogenic?

RYR1 p.Cys603Arg (c.1807T>C) is classified Uncertain significance in RYR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely benign (0.2796); Very rare (popmax 0.000508%, nfe); Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with RYR1 p.Cys603Arg (c.1807T>C)?

RYR1 p.Cys603Arg (c.1807T>C) is associated with malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Cys603Arg (c.1807T>C) in the general population?

RYR1 p.Cys603Arg (c.1807T>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about RYR1 p.Cys603Arg (c.1807T>C)?

AlphaMissense predicts likely benign (score 0.2796) — an in-silico prediction, not a clinical call.

RYR1 p.Cys603Arg

c.1807T>C · VCV3387657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

malignant hyperthermia, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.2796	likely benign
REVEL	0.775	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 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 8.1e-10 · regional, not allelic
Overall
CADD	24.8	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 0.000508% European (non-Finnish) · 6/1,180,022 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,158 alleles · very rare exomes 6/1,461,884 · genomes 0/152,274 · 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.Cys603Arg
Coding: c.1807T>C
MANE Select: NM_000540
Type: single nucleotide variant
Location: chr19:38457512 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 603: the b30.2/spry 1 domain

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.Cys603Tyr Uncertain significance ★ ⚠ same residue
RYR1 p.Cys603fs Uncertain significance ★ same residue
RYR1 p.Cys603= 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

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-cys603arg (accessed [today's date]).

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