Is RYR1 p.Pro4468= (c.13404C>T) pathogenic?

RYR1 p.Pro4468= (c.13404C>T) is classified Likely benign in RYR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-23). Ultra-rare (popmax 0.0247%, mid); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Pro4468= (c.13404C>T)?

RYR1 p.Pro4468= (c.13404C>T) is associated with RYR1-related disorder (ClinVar).

How common is RYR1 p.Pro4468= (c.13404C>T) in the general population?

RYR1 p.Pro4468= (c.13404C>T) is ultra-rare (popmax 0.0247%, mid) (gnomAD).

RYR1 p.Pro4468=

c.13404C>T · rs1973388711 · VCV2919186

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0247%, mid)

Conditions

RYR1-related disorder

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 -3.8	GERP -2.5
Overall
CADD	2.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0247% Middle Eastern · 1/4,042 alleles

Filtering AF 0.00393% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00234%

Overall 0.00035% 5/1,426,814 alleles · ultra-rare exomes 5/1,274,598 · genomes 0/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0247%	4,042
East Asian	0.0117%	8,523

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.Pro4468=
Coding: c.13404C>T
MANE Select: NM_000540
dbSNP: rs1973388711
Type: single nucleotide variant
Location: chr19:38565738 (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

RYR1-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RYR1 p.Pro4468Thr Uncertain significance ★★ same residue
RYR1 p.Pro4468Ser Uncertain significance ★ same residue
RYR1 c.10627-1G>C Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.14647-1G>C Likely pathogenic ★★ same condition
RYR1 c.14869-1G>T Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.2683-1G>A Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.2870+1G>A Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.3381+1G>A 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-pro4468 (accessed [today's date]).

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