Is RYR1 p.Ser604Pro (c.1810T>C) pathogenic?

RYR1 p.Ser604Pro (c.1810T>C) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-08). AlphaMissense: likely pathogenic (0.9961); Absent from gnomAD v4.1; Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Ser604Pro (c.1810T>C)?

RYR1 p.Ser604Pro (c.1810T>C) is associated with RYR1-related disorder, malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Ser604Pro (c.1810T>C) in the general population?

RYR1 p.Ser604Pro (c.1810T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR1 p.Ser604Pro (c.1810T>C)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

RYR1 p.Ser604Pro

c.1810T>C · rs901536375 · VCV594411

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic · top 5% in RYR1
REVEL	0.951	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; 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	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ser604Pro
Coding: c.1810T>C
MANE Select: NM_000540
dbSNP: rs901536375
Type: single nucleotide variant
Location: chr19:38457515 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 604: the b30.2/spry 1 domain

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 p.Ser604Phe Uncertain significance ★★ ⚠ same residue
RYR1 p.Ser604= 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-ser604pro (accessed [today's date]).

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