Is RYR1 p.Ser1007Arg (c.3021C>G) pathogenic?

RYR1 p.Ser1007Arg (c.3021C>G) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-23). AlphaMissense: likely pathogenic (0.9865); Very rare (popmax 0.00267%, afr); Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with RYR1 p.Ser1007Arg (c.3021C>G)?

RYR1 p.Ser1007Arg (c.3021C>G) is associated with malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Ser1007Arg (c.3021C>G) in the general population?

RYR1 p.Ser1007Arg (c.3021C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about RYR1 p.Ser1007Arg (c.3021C>G)?

AlphaMissense predicts likely pathogenic (score 0.9865) — an in-silico prediction, not a clinical call.

RYR1 p.Ser1007Arg

c.3021C>G · rs143891703 · VCV2637858

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

malignant hyperthermia, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.9865	likely pathogenic
REVEL	0.583	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.7
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 8.1e-10 · regional, not allelic
Overall
CADD	0.238	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 0.00267% African / African-American · 2/74,928 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,238 alleles · very rare exomes 1/1,461,044 · genomes 1/152,194 · 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.Ser1007Arg
Coding: c.3021C>G
MANE Select: NM_000540
dbSNP: rs143891703
Type: single nucleotide variant
Location: chr19:38466241 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1007: the '6 x approximate repeats' 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.Ser1007= 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
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-ser1007arg (accessed [today's date]).

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