Is RYR1 p.Pro4488= (c.13464G>A) pathogenic?

RYR1 p.Pro4488= (c.13464G>A) is classified Benign/Likely benign in RYR1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-26). Low-frequency (popmax 2.53%, afr); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Pro4488= (c.13464G>A)?

RYR1 p.Pro4488= (c.13464G>A) is associated with RYR1-related disorder, malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro4488= (c.13464G>A) in the general population?

RYR1 p.Pro4488= (c.13464G>A) is low-frequency (popmax 2.53%, afr) (gnomAD).

RYR1 p.Pro4488=

c.13464G>A · rs10405232 · VCV159835

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.53%, afr)

Conditions

RYR1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.4	GERP -3.5
Overall
CADD	0.346	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.53% African / African-American · 1,898/74,960 alleles

Filtering AF 2.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.4%

Overall 0.136% 2,182/1,605,876 alleles · low-frequency exomes 1,059/1,453,648 · genomes 1,123/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.53%	39
Admixed American	0.192%	520
Remaining individualsnot grpmax-eligible	0.174%	576
Middle Eastern	0.0331%	3,022
South Asian	0.0157%	6,384
European (non-Finnish)	0.00391%	25,576
East Asian	0.00224%	44,570

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.Pro4488=
Coding: c.13464G>A
MANE Select: NM_000540
dbSNP: rs10405232
Type: single nucleotide variant
Location: chr19:38566937 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4488: the 'disordered' region

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.Pro4488Leu Uncertain significance ★ ⚠ same residue
RYR1 p.Pro4488Ser 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

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-pro4488 (accessed [today's date]).

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