Is RYR1 p.Pro4495Ser (c.13483C>T) pathogenic?

RYR1 p.Pro4495Ser (c.13483C>T) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-16). AlphaMissense: likely benign (0.101); Ultra-rare (popmax 0.0187%, amr); Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with RYR1 p.Pro4495Ser (c.13483C>T)?

RYR1 p.Pro4495Ser (c.13483C>T) is associated with malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Pro4495Ser (c.13483C>T) in the general population?

RYR1 p.Pro4495Ser (c.13483C>T) is ultra-rare (popmax 0.0187%, amr) (gnomAD).

What do computational predictors say about RYR1 p.Pro4495Ser (c.13483C>T)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

RYR1 p.Pro4495Ser

c.13483C>T · rs767437276 · VCV1408482

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

malignant hyperthermia, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.255	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 0.35	GERP 0.83, phastCons 0.13
Regional constraint	o/e 0.99	unconstrained · MANE · 22 kb · p 0.81 · regional, not allelic
Overall
CADD	5.719	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 0.0187% Admixed American · 11/58,720 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.000934% 15/1,605,490 alleles · ultra-rare exomes 11/1,453,238 · genomes 4/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0187%	5,338
Remaining individualsnot grpmax-eligible	0.00644%	15,530

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.Pro4495Ser
Coding: c.13483C>T
MANE Select: NM_000540
dbSNP: rs767437276
Type: single nucleotide variant
Location: chr19:38566956 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4495: the 'disordered' region

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

Similar variants

RYR1 p.Pro4495Arg Uncertain significance ★★ ⚠ same residue
RYR1 p.Pro4495Leu Uncertain significance ★★ ⚠ same residue
RYR1 p.Pro4495= Likely benign ★★ same residue
RYR1 p.Pro4495Gln Likely benign ★ 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

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-pro4495ser (accessed [today's date]).

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