Is RYR2 p.Leu4026Val (c.12076T>G) pathogenic?

RYR2 p.Leu4026Val (c.12076T>G) is classified Conflicting classifications of pathogenicity in RYR2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2242); Ultra-rare (popmax 0.012%, afr); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Leu4026Val (c.12076T>G)?

RYR2 p.Leu4026Val (c.12076T>G) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Leu4026Val (c.12076T>G) in the general population?

RYR2 p.Leu4026Val (c.12076T>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about RYR2 p.Leu4026Val (c.12076T>G)?

AlphaMissense predicts likely benign (score 0.2242) — an in-silico prediction, not a clinical call.

RYR2 p.Leu4026Val

c.12076T>G · rs765141566 · VCV463552

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2242	likely benign
REVEL	0.544	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 -0.52	GERP -1.6
Regional constraint	o/e 0.82	unconstrained · MANE · 184 bp · p 0.1 · regional, not allelic
Overall
CADD	13.67	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 0.012% African / African-American · 9/74,946 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000744% 12/1,613,396 alleles · ultra-rare exomes 5/1,461,156 · genomes 7/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,327
Admixed American	0.00334%	29,983
Remaining individualsnot grpmax-eligible	0.0016%	62,446

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.Leu4026Val
Coding: c.12076T>G
MANE Select: NM_001035
dbSNP: rs765141566
Type: single nucleotide variant
Location: chr1:237783788 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4026: an α-helix

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

Disease context

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

Also linked: cardiomyopathy catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia

Similar variants

RYR2 p.Leu4026Trp 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-leu4026val (accessed [today's date]).

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