TNNI3K
Chr 1ADTNNI3 interacting kinase
Also known as: CARK, CCDD
This gene encodes a MAP kinase kinase kinase (MAPKKK) family protein kinase with ankyrin repeat, protein kinase and serine-rich domains that functions in cardiac physiology. Mutations cause autosomal dominant cardiac conduction disease with or without dilated cardiomyopathy. The gene shows low constraint against loss-of-function variants (pLI near zero, LOEUF 1.43), suggesting that complete loss of protein function may be tolerated.
Primary Disease Associations & Inheritance
Moderate evidence — consider for supplementary testing
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 4 | 0 | 4 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 24 | 261 | 40 | 8 | 333 |
Likely Benign | 0 | 6 | 89 | 59 | 154 |
Benign | 0 | 0 | 4 | 0 | 4 |
Conflicting | — | 2 | |||
| Total | 24 | 267 | 138 | 67 | 498 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TNNI3K · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools