Is RYR2 p.Pro3232Ser (c.9694C>T) pathogenic?

RYR2 p.Pro3232Ser (c.9694C>T) is classified Uncertain significance in RYR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-23). AlphaMissense: likely pathogenic (0.6952); Very rare (popmax 8.48e-05%, nfe); Associated with cardiomyopathy.

What condition is associated with RYR2 p.Pro3232Ser (c.9694C>T)?

RYR2 p.Pro3232Ser (c.9694C>T) is associated with cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Pro3232Ser (c.9694C>T) in the general population?

RYR2 p.Pro3232Ser (c.9694C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RYR2 p.Pro3232Ser (c.9694C>T)?

AlphaMissense predicts likely pathogenic (score 0.6952) — an in-silico prediction, not a clinical call.

RYR2 p.Pro3232Ser

c.9694C>T · rs1688442582 · VCV842265

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.6952	likely pathogenic
REVEL	0.586	indeterminate
SaProt	—	not scored · why
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 0.81	unconstrained · MANE · 132 kb · p 8.2e-16 · regional, not allelic
Overall
CADD	21.9	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 8.48e-05% European (non-Finnish) · 1/1,179,822 alleles

Overall 0.000124% 2/1,613,850 alleles · very rare exomes 2/1,461,644 · genomes 0/152,206 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,996
European (non-Finnish)grpmax	8.48e-05%	1,179,823

Finnish 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: RYR2
Protein: p.Pro3232Ser
Coding: c.9694C>T
MANE Select: NM_001035
dbSNP: rs1688442582
Type: single nucleotide variant
Location: chr1:237707062 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)

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

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: catecholaminergic polymorphic ventricular tachycardia 1

Similar variants

RYR2 p.Pro3232= Likely benign ★★ same residue
RYR2 p.Ala2387Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala2387Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala391Asp Likely pathogenic ★★ same condition
RYR2 p.Ala4091Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala4510Pro Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala77Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg169Gln Pathogenic/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/ryr2-p-pro3232ser (accessed [today's date]).

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