# NM_001035.3(RYR2):c.12076T>G (p.Leu4026Val)

https://sugi.bio/variant/ryr2-p-leu4026val

## Summary

**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.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs765141566 · 5 submitters · 4 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.012%, afr)

## For patients & families {#patients}

This is a change in the RYR2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to Cardiovascular phenotype.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RYR2](https://sugi.bio/atlas/gene/RYR2/) |
| Protein change (HGVS p.) | p.Leu4026Val |
| Coding change (HGVS c.) | c.12076T>G |
| MANE Select transcript | [NM_001035](https://www.ncbi.nlm.nih.gov/nuccore/NM_001035) |
| dbSNP | [rs765141566](https://www.ncbi.nlm.nih.gov/snp/rs765141566/) |
| Variant type | single nucleotide variant |
| Location | chr1:237783788-237783788 (GRCh38) |
| ClinVar | [VCV463552](https://www.ncbi.nlm.nih.gov/clinvar/variation/463552/) |

**All HGVS expressions:** `LRG_402:g.746605T>G`, `LRG_402t1:c.12076T>G`, `NC_000001.10:g.237947088T>G`, `NC_000001.11:g.237783788T>G`, `NG_008799.3:g.746605T>G`, `NM_001035.3:c.12076T>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2242)
- REVEL 0.544 (indeterminate)
- Conservation: phyloP -0.515, GERP -1.64 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 13.67**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.82** across the covering region of the MANE Select transcript (237,783,785–237,783,969), spanning 184 bp. Chi-square p 0.1. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for RYR2 (7,383 scored positions, the nearest 6 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.012%** (afr) · FAF95 0.00623% · FAF99 0.00467% · 9/74,946 in the highest group · 12/1,613,396 alleles overall — ultra-rare (popmax 0.012%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.012% | 8,327 |
| Admixed American | 0.00334% | 29,983 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,446 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**RYR2** population constraint: LOEUF 0.424, pLI 1, missense-Z 6.4389; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **catecholaminergic polymorphic ventricular tachycardia** — Definitive (AD)
- **hypertrophic cardiomyopathy** — Limited (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Refuted (AD)
- **dilated cardiomyopathy** — Limited (AD)

## Protein context {#protein}

Residue **4026** lies in an α-helix.

**26 experimental structure(s)** (PDB): [4JKQ](https://www.rcsb.org/structure/4JKQ), [6Y4O](https://www.rcsb.org/structure/6Y4O), [6Y4P](https://www.rcsb.org/structure/6Y4P), [7KL5](https://www.rcsb.org/structure/7KL5), [7U9Q](https://www.rcsb.org/structure/7U9Q), [7U9R](https://www.rcsb.org/structure/7U9R) — incl. mutant structure 6Y4P.

## What this gene does {#gene-function}

*Describes the biological roles of RYR2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** RYR2's established molecular role includes ryanodine-sensitive calcium-release channel activity.


### Pathways affected {#pathways}

RYR2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ryanodine-sensitive calcium-release channel activity, calmodulin binding, intracellularly gated calcium channel activity, enzyme binding, protein kinase A catalytic subunit binding, protein kinase A regulatory subunit binding.

**Biological process:** regulation of heart rate, detection of calcium ion, calcium ion transport, regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion, regulation of cardiac muscle contraction by calcium ion signaling, release of sequestered calcium ion into cytosol by sarcoplasmic reticulum.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign, 1 Uncertain Significance).

**Submission history:** 5 submissions (2023–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-11 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-06 |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-07-29 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-03 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [catecholaminergic polymorphic ventricular tachycardia 1](https://sugi.bio/atlas/disease/catecholaminergic-polymorphic-ventricular-tachycardia-1/), [catecholaminergic polymorphic ventricular tachycardia](https://sugi.bio/atlas/disease/catecholaminergic-polymorphic-ventricular-tachycardia/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Cardiomyopathy, Catecholaminergic polymorphic ventricular tachycardia 1, Catecholaminergic polymorphic ventricular tachycardia, not provided, Catecholamine-induced polymorphic ventricular tachycardia, none provided, Cardiomyopathies, VENTRICULAR TACHYCARDIA, STRESS-INDUCED POLYMORPHIC 1, VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY.

## Similar variants {#similar}

Related RYR2 variant pages (same residue, condition, or type): [RYR2 p.Leu4026Trp](/variant/ryr2-p-leu4026trp), [RYR2 p.Ala2387Thr](/variant/ryr2-p-ala2387thr), [RYR2 p.Ala2387Val](/variant/ryr2-p-ala2387val), [RYR2 p.Ala391Asp](/variant/ryr2-p-ala391asp), [RYR2 p.Ala4091Val](/variant/ryr2-p-ala4091val), [RYR2 p.Ala4510Pro](/variant/ryr2-p-ala4510pro), [RYR2 p.Ala77Val](/variant/ryr2-p-ala77val), [RYR2 p.Arg169Gln](/variant/ryr2-p-arg169gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 463552). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*