Is RYR1 p.Phe3552= (c.10656T>C) pathogenic?

RYR1 p.Phe3552= (c.10656T>C) is classified Conflicting classifications of pathogenicity in RYR1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-11-30). Absent from gnomAD v4.1; Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with RYR1 p.Phe3552= (c.10656T>C)?

RYR1 p.Phe3552= (c.10656T>C) is associated with malignant hyperthermia, susceptibility to, 1, central core myopathy, congenital multicore myopathy with external ophthalmoplegia (ClinVar).

How common is RYR1 p.Phe3552= (c.10656T>C) in the general population?

RYR1 p.Phe3552= (c.10656T>C) is absent from gnomAD v4.1 (gnomAD).

RYR1 p.Phe3552=

c.10656T>C · rs1971495978 · VCV889885

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

malignant hyperthermia, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.5, phastCons 1
Overall
CADD	15.25	PHRED · no single calibrated threshold — expert panels disagree

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.Phe3552=
Coding: c.10656T>C
MANE Select: NM_000540
dbSNP: rs1971495978
Type: single nucleotide variant
Location: chr19:38527022 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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

Also linked: central core myopathy congenital multicore myopathy with external ophthalmoplegia

Similar variants

RYR1 p.Phe3552Val Uncertain significance ★ 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-phe3552 (accessed [today's date]).

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