Is RYR2 p.Val2178= (c.6534C>T) pathogenic?

RYR2 p.Val2178= (c.6534C>T) is classified Likely benign in RYR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-06). Ultra-rare (popmax 0.0166%, mid); Associated with cardiomyopathy.

How common is RYR2 p.Val2178= (c.6534C>T) in the general population?

RYR2 p.Val2178= (c.6534C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

RYR2 p.Val2178=

Q: What condition is associated with RYR2 p.Val2178= (c.6534C>T)?

RYR2 p.Val2178= (c.6534C>T) is associated with cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia (ClinVar).

c.6534C>T · rs904724019 · VCV463619

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.017	GERP -3.4, phastCons 0.85
Overall
CADD	3.731	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,042 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00072%

Overall 0.00131% 21/1,607,016 alleles · ultra-rare exomes 19/1,456,972 · genomes 2/150,044 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,042
Remaining individualsnot grpmax-eligible	0.00483%	20,703
European (non-Finnish)	0.00144%	69,207

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.Val2178=
Coding: c.6534C>T
MANE Select: NM_001035
dbSNP: rs904724019
Type: single nucleotide variant
Location: chr1:237631520 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2178: the '4 x approximate repeats' region; an α-helix

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.Val2178Ile Conflicting classifications of pathogenicity ★ ⚠ 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-val2178 (accessed [today's date]).

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