Is RYR2 p.Val686= (c.2058G>T) pathogenic?

RYR2 p.Val686= (c.2058G>T) is classified Uncertain significance in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). Absent from gnomAD v4.1; Associated with catecholaminergic polymorphic ventricular tachycardia.

What condition is associated with RYR2 p.Val686= (c.2058G>T)?

RYR2 p.Val686= (c.2058G>T) is associated with catecholaminergic polymorphic ventricular tachycardia (ClinVar).

How common is RYR2 p.Val686= (c.2058G>T) in the general population?

RYR2 p.Val686= (c.2058G>T) is absent from gnomAD v4.1 (gnomAD).

RYR2 p.Val686=

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.2058G>T · rs2545835836 · VCV3072495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

catecholaminergic polymorphic ventricular tachycardia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.84	acceptor gain · deltas
Pangolin	Δ0.35	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP 1, phastCons 1
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RYR2
Protein: p.Val686=
Coding: c.2058G>T
MANE Select: NM_001035
dbSNP: rs2545835836
Type: single nucleotide variant
Location: chr1:237496607 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 686: the b30.2/spry 1 domain; a β-strand

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.Val686Met Uncertain significance ★★ same residue
RYR2 p.Val686Gly Uncertain significance ★★ ⚠ same residue
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

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-val686 (accessed [today's date]).

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