Is RYR1 p.Pro4472Ser (c.13414C>T) pathogenic?

RYR1 p.Pro4472Ser (c.13414C>T) is classified Uncertain significance in RYR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely pathogenic (0.6478); Very rare (popmax 0.00301%, afr); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Pro4472Ser (c.13414C>T)?

RYR1 p.Pro4472Ser (c.13414C>T) is associated with RYR1-related disorder (ClinVar).

How common is RYR1 p.Pro4472Ser (c.13414C>T) in the general population?

RYR1 p.Pro4472Ser (c.13414C>T) is very rare (popmax 0.00301%, afr) (gnomAD).

What do computational predictors say about RYR1 p.Pro4472Ser (c.13414C>T)?

AlphaMissense predicts likely pathogenic (score 0.6478) — an in-silico prediction, not a clinical call.

RYR1 p.Pro4472Ser

c.13414C>T · rs1478455921 · VCV2862732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00301%, afr)

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.6478	likely pathogenic
REVEL	0.426	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 22 kb · p 0.81 · regional, not allelic
Overall
CADD	21.4	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 0.00301% African / African-American · 2/66,414 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000187%

Overall 0.000211% 3/1,420,114 alleles · very rare exomes 0/1,268,012 · genomes 3/152,102 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00301%	33,207
Finnishnot grpmax-eligible	0.00238%	41,980

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.Pro4472Ser
Coding: c.13414C>T
MANE Select: NM_000540
dbSNP: rs1478455921
Type: single nucleotide variant
Location: chr19:38565748 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4472: 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.Pro4472Arg Uncertain significance ★★ same residue
RYR1 p.Pro4472= 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-pro4472ser (accessed [today's date]).

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