Atrial conduction disease

Summary

Atrial conduction disease (MONDO:0014500) is a disease caused by TNNI3K (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TNNI3K (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 77

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial conduction disease
Mondo ID	MONDO:0014500
EFO	EFO:0005304
GARD	0017729
Is cancer (heuristic)	no

Also known as: CARDIAC conduction disease with or without dilated cardiomyopathy · CCDD

Data availability: 77 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › conduction system disorder › atrial conduction disease

Related subtypes (3): sinoatrial node disorder, atrioventricular node disorder, progressive familial heart block, type 1A

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

77 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 10 benign, 9 benign/likely benign, 8 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
626247	NM_015978.3(TNNI3K):c.2302G>A (p.Glu768Lys)	FPGT-TNNI3K	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161447	NM_015978.3(TNNI3K):c.1577G>A (p.Gly526Asp)	FPGT-TNNI3K	Likely pathogenic	criteria provided, single submitter
590304	NM_015978.3(TNNI3K):c.1615A>G (p.Thr539Ala)	FPGT-TNNI3K	Likely pathogenic	criteria provided, single submitter
1297714	NM_015978.3(TNNI3K):c.465A>G (p.Gln155=)	FPGT-TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1545733	NM_015978.3(TNNI3K):c.1772G>C (p.Ser591Thr)	FPGT-TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1548942	NM_015978.3(TNNI3K):c.2128C>A (p.Pro710Thr)	FPGT-TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1590549	NM_015978.3(TNNI3K):c.1550A>G (p.Asn517Ser)	FPGT-TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1599675	NM_015978.3(TNNI3K):c.193G>T (p.Glu65Ter)	FPGT-TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1802225	NM_015978.3(TNNI3K):c.538G>T (p.Glu180Ter)	FPGT-TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3234925	NM_015978.3(TNNI3K):c.2222C>A (p.Ser741Ter)	FPGT-TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1373602	NM_015978.3(TNNI3K):c.2297G>C (p.Arg766Pro)	TNNI3K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1302410	NM_015978.3(TNNI3K):c.1153T>C (p.Cys385Arg)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1307801	NM_015978.3(TNNI3K):c.1561G>A (p.Val521Ile)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1308510	NM_015978.3(TNNI3K):c.2012C>T (p.Ala671Val)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356605	NM_015978.3(TNNI3K):c.680A>T (p.Asp227Val)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1377654	NM_015978.3(TNNI3K):c.380T>C (p.Ile127Thr)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1406963	NM_015978.3(TNNI3K):c.1097T>C (p.Met366Thr)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1423033	NM_015978.3(TNNI3K):c.2053C>T (p.Pro685Ser)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1427017	NM_015978.3(TNNI3K):c.929A>T (p.His310Leu)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1431414	NM_015978.3(TNNI3K):c.681T>C (p.Asp227=)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1433379	NM_015978.3(TNNI3K):c.278G>A (p.Arg93His)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1436703	NM_015978.3(TNNI3K):c.1400A>G (p.Glu467Gly)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1464261	NM_015978.3(TNNI3K):c.1411T>C (p.Ser471Pro)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1474167	NM_015978.3(TNNI3K):c.912C>G (p.Phe304Leu)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1477156	NM_015978.3(TNNI3K):c.2269C>T (p.Arg757Trp)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1478307	NM_015978.3(TNNI3K):c.404T>C (p.Leu135Pro)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1496771	NM_015978.3(TNNI3K):c.1471C>T (p.Arg491Cys)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1514392	NM_015978.3(TNNI3K):c.175A>G (p.Asn59Asp)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1520068	NM_015978.3(TNNI3K):c.1076T>G (p.Leu359Ter)	FPGT-TNNI3K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679708	NM_015978.3(TNNI3K):c.2121+7526_2121+7529dup	FPGT-TNNI3K	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TNNI3K	Strong	Autosomal dominant	atrial conduction disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNI3K	Orphanet:436242	Hereditary atrial tachyarrhythmia-infra-Hisian cardiac conduction disease

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNI3K	HGNC:19661	ENSG00000116783	Q59H18	Serine/threonine-protein kinase TNNI3K	gencc,clinvar
FPGT-TNNI3K	HGNC:42952	ENSG00000259030		FPGT-TNNI3K readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNI3K	Serine/threonine-protein kinase TNNI3K	May play a role in cardiac physiology.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNI3K	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ankyrin_rpt
FPGT-TNNI3K	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart left ventricle	1
right atrium auricular region	1
calcaneal tendon	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNI3K	134	tissue_specific	marker	apex of heart, heart left ventricle, right atrium auricular region
FPGT-TNNI3K	134	ubiquitous	yes	calcaneal tendon, corpus callosum, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNNI3K	1,430
FPGT-TNNI3K	0

Intra-cohort edges

A	B	Sources
FPGT-TNNI3K	TNNI3K	biogrid_interaction

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNI3K	Q59H18	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bundle of His cell to Purkinje myocyte communication	1	16852.0×	4e-04	TNNI3K
peptidyl-serine autophosphorylation	1	3370.4×	9e-04	TNNI3K
regulation of cardiac muscle contraction	1	887.0×	0.002	TNNI3K
regulation of cardiac conduction	1	842.6×	0.002	TNNI3K
regulation of heart rate	1	468.1×	0.003	TNNI3K
protein phosphorylation	1	68.0×	0.015	TNNI3K

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TNNI3K	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNNI3K	20	4
FPGT-TNNI3K	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	TNNI3K
SORAFENIB	4	TNNI3K
VANDETANIB	4	TNNI3K
NILOTINIB	4	TNNI3K
BOSUTINIB	4	TNNI3K
DASATINIB	4	TNNI3K
ERLOTINIB	4	TNNI3K
CRIZOTINIB	4	TNNI3K
IMATINIB	4	TNNI3K
CANERTINIB	3	TNNI3K
ALVOCIDIB	3	TNNI3K
MOTESANIB	3	TNNI3K
LESTAURTINIB	3	TNNI3K
FORETINIB	2	TNNI3K
TG100-115	2	TNNI3K
RG-547	2	TNNI3K
R-406	2	TNNI3K
RAF-265	2	TNNI3K
PELITINIB	2	TNNI3K
AST-487	1	TNNI3K

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TNNI3K	92	Binding:92

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

20 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	TNNI3K
SORAFENIB	4	TNNI3K
VANDETANIB	4	TNNI3K
NILOTINIB	4	TNNI3K
BOSUTINIB	4	TNNI3K
DASATINIB	4	TNNI3K
ERLOTINIB	4	TNNI3K
CRIZOTINIB	4	TNNI3K
IMATINIB	4	TNNI3K
CANERTINIB	3	TNNI3K
ALVOCIDIB	3	TNNI3K
MOTESANIB	3	TNNI3K
LESTAURTINIB	3	TNNI3K
FORETINIB	2	TNNI3K
TG100-115	2	TNNI3K
RG-547	2	TNNI3K
R-406	2	TNNI3K
RAF-265	2	TNNI3K
PELITINIB	2	TNNI3K
AST-487	1	TNNI3K

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TNNI3K
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FPGT-TNNI3K

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FPGT-TNNI3K	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.