Is RYR2 p.Pro1496= (c.4488C>T) pathogenic?

RYR2 p.Pro1496= (c.4488C>T) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-26). Very rare (popmax 0.00805%, nfe); Associated with cardiomyopathy.

How common is RYR2 p.Pro1496= (c.4488C>T) in the general population?

RYR2 p.Pro1496= (c.4488C>T) is very rare (popmax 0.00805%, nfe) (gnomAD).

RYR2 p.Pro1496=

Q: What condition is associated with RYR2 p.Pro1496= (c.4488C>T)?

RYR2 p.Pro1496= (c.4488C>T) is associated with cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia (ClinVar).

c.4488C>T · rs370082063 · VCV378488

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00805%, nfe)

Conditions

cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4
Overall
CADD	4.205	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00805% European (non-Finnish) · 95/1,179,700 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00625%

Overall 0.00676% 109/1,613,562 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,668
European (non-Finnish)grpmax	0.00805%	12,418
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00267%	37,512
East Asian	0.00223%	44,832
Admixed American	0.00167%	59,980
South Asian	0.0011%	90,970

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.Pro1496=
Coding: c.4488C>T
MANE Select: NM_001035
dbSNP: rs370082063
Type: single nucleotide variant
Location: chr1:237595549 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1496: the b30.2/spry 3 domain; the '4 x approximate repeats' region; a β-strand

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 catecholaminergic polymorphic ventricular tachycardia

Similar variants

RYR2 p.Pro1496Leu Uncertain significance ★ 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-pro1496 (accessed [today's date]).

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