Is RYR1 p.Pro2001Arg (c.6002C>G) pathogenic?

RYR1 p.Pro2001Arg (c.6002C>G) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-26). AlphaMissense: likely pathogenic (0.9599); Absent from gnomAD v4.1; Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Pro2001Arg (c.6002C>G)?

RYR1 p.Pro2001Arg (c.6002C>G) is associated with RYR1-related disorder, malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro2001Arg (c.6002C>G) in the general population?

RYR1 p.Pro2001Arg (c.6002C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR1 p.Pro2001Arg (c.6002C>G)?

AlphaMissense predicts likely pathogenic (score 0.9599) — an in-silico prediction, not a clinical call.

RYR1 p.Pro2001Arg

c.6002C>G · rs760559322 · VCV1487706

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9599 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9599	likely pathogenic
REVEL	0.542	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 8.1e-10 · regional, not allelic
Overall
CADD	21.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RYR1
Protein: p.Pro2001Arg
Coding: c.6002C>G
MANE Select: NM_000540
dbSNP: rs760559322
Type: single nucleotide variant
Location: chr19:38490263 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2001: the '6 x approximate repeats' region

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 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
RYR1 p.Ala2437Val 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-pro2001arg (accessed [today's date]).

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