Is RYR2 p.Pro4641Ala (c.13921C>G) pathogenic?

RYR2 p.Pro4641Ala (c.13921C>G) is classified Uncertain significance in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). AlphaMissense: likely pathogenic (0.9711); Very rare (popmax 0.000294%, nfe); Associated with catecholaminergic polymorphic ventricular tachycardia.

What condition is associated with RYR2 p.Pro4641Ala (c.13921C>G)?

RYR2 p.Pro4641Ala (c.13921C>G) is associated with catecholaminergic polymorphic ventricular tachycardia (ClinVar).

How common is RYR2 p.Pro4641Ala (c.13921C>G) in the general population?

RYR2 p.Pro4641Ala (c.13921C>G) is very rare (popmax 0.000294%, nfe) (gnomAD).

What do computational predictors say about RYR2 p.Pro4641Ala (c.13921C>G)?

AlphaMissense predicts likely pathogenic (score 0.9711) — an in-silico prediction, not a clinical call.

RYR2 p.Pro4641Ala

Q: How is Catecholaminergic polymorphic ventricular tachycardia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.13921C>G · rs1259504346 · VCV3072478

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000294%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

catecholaminergic polymorphic ventricular tachycardia

Computational evidence

Protein change
AlphaMissense	0.9711	likely pathogenic
REVEL	0.813	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; 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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 5,796 bp · p 8.5e-11 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000294% European (non-Finnish) · 3/1,018,918 alleles

Filtering AF 7.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2e-05%

Overall 0.000214% 3/1,401,520 alleles · very rare exomes 2/1,249,590 · genomes 1/151,930 · joint denominator

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: RYR2
Protein: p.Pro4641Ala
Coding: c.13921C>G
MANE Select: NM_001035
dbSNP: rs1259504346
Type: single nucleotide variant
Location: chr1:237795296 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4641: a turn

Full RYR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

catecholaminergic polymorphic ventricular tachycardia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Catecholaminergic polymorphic ventricular tachycardia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

RYR2 p.Ala2387Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg169Gln Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg420Trp Pathogenic ★★ same condition
RYR2 p.Ile4867Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Leu433Pro Pathogenic ★★ same condition
RYR2 p.Tyr4725Cys Pathogenic/Likely pathogenic ★★ same condition
RYR2 c.10494+1G>T Uncertain significance ★★ same condition
RYR2 c.10555-3C>A Uncertain significance ★★ 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/ryr2-p-pro4641ala (accessed [today's date]).

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