Is RYR1 p.Pro4493Ala (c.13477C>G) pathogenic?

RYR1 p.Pro4493Ala (c.13477C>G) is classified Conflicting classifications of pathogenicity in RYR1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0663); Rare (popmax 0.114%, amr); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Pro4493Ala (c.13477C>G)?

RYR1 p.Pro4493Ala (c.13477C>G) is associated with RYR1-related disorder, central core myopathy, malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro4493Ala (c.13477C>G) in the general population?

RYR1 p.Pro4493Ala (c.13477C>G) is rare (popmax 0.114%, amr) (gnomAD).

What do computational predictors say about RYR1 p.Pro4493Ala (c.13477C>G)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

RYR1 p.Pro4493Ala

c.13477C>G · rs149455643 · VCV478185

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.25	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 22 kb · p 0.81 · regional, not allelic
Overall
CADD	8.838	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

Grpmax group 0.114% Admixed American · 67/58,830 alleles

Filtering AF 0.092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.084%

Overall 0.0275% 441/1,606,206 alleles · rare exomes 409/1,454,062 · genomes 32/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.114%	878
Remaining individualsnot grpmax-eligible	0.0338%	2,958
European (non-Finnish)	0.0296%	3,381
African / African-American	0.00668%	14,970

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.Pro4493Ala
Coding: c.13477C>G
MANE Select: NM_000540
dbSNP: rs149455643
Type: single nucleotide variant
Location: chr19:38566950 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4493: a UniProt-annotated variant site (in); the 'disordered' region

Full RYR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: central core myopathy malignant hyperthermia, susceptibility to, 1 congenital fiber-type disproportion myopathy congenital multicore myopathy with external ophthalmoplegia

Similar variants

RYR1 p.Pro4493Ser Uncertain significance ★★ ⚠ same residue
RYR1 p.Pro4493= Likely benign ★★ same residue
RYR1 p.Pro4493His 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

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-pro4493ala (accessed [today's date]).

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