Is RYR1 p.Pro4489Ser (c.13465C>T) pathogenic?

RYR1 p.Pro4489Ser (c.13465C>T) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.0807); Very rare (popmax 0.00314%, nfe); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Pro4489Ser (c.13465C>T)?

RYR1 p.Pro4489Ser (c.13465C>T) is associated with RYR1-related disorder, central core myopathy, malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro4489Ser (c.13465C>T) in the general population?

RYR1 p.Pro4489Ser (c.13465C>T) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about RYR1 p.Pro4489Ser (c.13465C>T)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

RYR1 p.Pro4489Ser

c.13465C>T · rs781766697 · VCV965229

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.276	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 22 kb · p 0.81 · regional, not allelic
Overall
CADD	12.42	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00314% European (non-Finnish) · 37/1,176,720 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00261% 42/1,606,144 alleles · very rare exomes 36/1,454,058 · genomes 6/152,086 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00644%	15,538
European (non-Finnish)grpmax	0.00314%	31,803
African / African-American	0.00134%	74,836

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro4489Ser
Coding: c.13465C>T
MANE Select: NM_000540
dbSNP: rs781766697
Type: single nucleotide variant
Location: chr19:38566938 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4489: 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 King-Denborough syndrome

Similar variants

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
RYR1 p.Ala2437Val 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-pro4489ser (accessed [today's date]).

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