Is RYR1 p.Pro4468Ser (c.13402C>T) pathogenic?

RYR1 p.Pro4468Ser (c.13402C>T) is classified Uncertain significance in RYR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-22). AlphaMissense: likely pathogenic (0.7712); No allele count reported in gnomAD v4.1 (AN 1,428,390); Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with RYR1 p.Pro4468Ser (c.13402C>T)?

RYR1 p.Pro4468Ser (c.13402C>T) is associated with malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro4468Ser (c.13402C>T) in the general population?

RYR1 p.Pro4468Ser (c.13402C>T) is no allele count reported in gnomAD v4.1 (AN 1,428,390) (gnomAD).

What do computational predictors say about RYR1 p.Pro4468Ser (c.13402C>T)?

AlphaMissense predicts likely pathogenic (score 0.7712) — an in-silico prediction, not a clinical call.

RYR1 p.Pro4468Ser

c.13402C>T · VCV3385595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7712 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,428,390)

Conditions

malignant hyperthermia, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.7712	likely pathogenic
REVEL	0.421	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 22 kb · p 0.81 · regional, not allelic
Overall
CADD	21.1	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

No allele count reported in gnomAD v4.1 (AN 1,428,390). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RYR1
Protein: p.Pro4468Ser
Coding: c.13402C>T
MANE Select: NM_000540
Type: single nucleotide variant
Location: chr19:38565736 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4468: the 'disordered' 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.Pro4468Thr Uncertain significance ★★ same residue
RYR1 p.Pro4468= 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-pro4468ser (accessed [today's date]).

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