Atrial fibrillation, familial, 11

Summary

Atrial fibrillation, familial, 11 (MONDO:0013544) is a disease caused by GJA5 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GJA5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 320

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial fibrillation, familial, 11
Mondo ID	MONDO:0013544
OMIM	614049
UMLS	C3279693
MedGen	481323
GARD	0015747
Is cancer (heuristic)	no

Also known as: ATFB11 · atrial fibrillation, familial, 11 · atrial fibrillation, familial, type 11 · familial atrial fibrillation caused by mutation in GJA5 · GJA5 familial atrial fibrillation

Data availability: 320 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › atrial fibrillation › familial atrial fibrillation › atrial fibrillation, familial, 11

Related subtypes (17): atrial fibrillation, familial, 3, atrial fibrillation, familial, 1, atrial fibrillation, familial, 2, atrial fibrillation, familial, 4, atrial fibrillation, familial, 5, atrial fibrillation, familial, 6, atrial fibrillation, familial, 7, atrial fibrillation, familial, 8, atrial fibrillation, familial, 9, atrial fibrillation, familial, 10, atrial fibrillation, familial, 12, atrial fibrillation, familial, 13, atrial fibrillation, familial, 14, atrial fibrillation, familial, 15, atrial fibrillation, familial, 18, atrial fibrillation, familial, 17, atrial fibrillation, familial, 16

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

320 retrieved; paginated sample, class counts are floors:

208 uncertain significance, 90 likely benign, 8 pathogenic, 8 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1444016	NC_000001.10:g.(?147230270)(147231346_?)del	GJA5	Pathogenic	criteria provided, single submitter
2042319	NM_181703.4(GJA5):c.23del (p.Gly8fs)	GJA5	Pathogenic	criteria provided, single submitter
29663	NM_181703.4(GJA5):c.145C>T (p.Gln49Ter)	GJA5	Pathogenic	no assertion criteria provided
29664	NM_181703.4(GJA5):c.253G>A (p.Val85Ile)	GJA5	Pathogenic	no assertion criteria provided
29666	NM_181703.4(GJA5):c.685C>A (p.Leu229Met)	GJA5	Pathogenic	no assertion criteria provided
3755327	NM_181703.4(GJA5):c.3G>A (p.Met1Ile)	GJA5	Pathogenic	criteria provided, single submitter
625769	GRCh37/hg19 1q21.2(chr1:147245049-147246661)	GJA5	Pathogenic	criteria provided, single submitter
29665	NM_181703.4(GJA5):c.661C>A (p.Leu221Ile)	LOC122128420	Pathogenic	no assertion criteria provided
2182825	NM_181703.4(GJA5):c.497G>C (p.Gly166Ala)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2639123	NM_181703.4(GJA5):c.932G>C (p.Gly311Ala)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292448	NM_181703.4(GJA5):c.995G>A (p.Arg332His)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292450	NM_181703.4(GJA5):c.353G>A (p.Arg118Gln)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292451	NM_181703.4(GJA5):c.342C>G (p.Ala114=)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292453	NM_181703.4(GJA5):c.13A>G (p.Ser5Gly)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
577662	NM_181703.4(GJA5):c.973A>C (p.Asn325His)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876990	NM_181703.4(GJA5):c.348G>A (p.Glu116=)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001932	NM_181703.4(GJA5):c.941A>G (p.Gln314Arg)	GJA5	Uncertain significance	criteria provided, single submitter
1018451	NM_181703.4(GJA5):c.199G>A (p.Asp67Asn)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034934	NM_181703.4(GJA5):c.525C>G (p.Tyr175Ter)	GJA5	Uncertain significance	criteria provided, single submitter
1038988	NM_181703.4(GJA5):c.278T>C (p.Met93Thr)	GJA5	Uncertain significance	criteria provided, single submitter
1056660	NM_181703.4(GJA5):c.1024C>T (p.Arg342Ter)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1062702	NM_181703.4(GJA5):c.170T>G (p.Ile57Ser)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
126903	NM_181703.4(GJA5):c.223A>T (p.Ile75Phe)	GJA5	Uncertain significance	criteria provided, single submitter
1316153	NM_181703.4(GJA5):c.977G>C (p.Gly326Ala)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1316776	NM_181703.4(GJA5):c.53C>T (p.Ser18Leu)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1317232	NM_181703.4(GJA5):c.359C>G (p.Ser120Cys)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1317266	NM_181703.4(GJA5):c.724C>T (p.Arg242Trp)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1318650	NM_181703.4(GJA5):c.356G>A (p.Gly119Asp)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1345427	NM_181703.4(GJA5):c.893C>G (p.Thr298Ser)	GJA5	Uncertain significance	criteria provided, single submitter
1347734	NM_181703.4(GJA5):c.229T>C (p.Tyr77His)	GJA5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
GJA5	Strong	Autosomal dominant	atrial fibrillation, familial, 11	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJA5	Orphanet:3303	Tetralogy of Fallot
GJA5	Orphanet:334	Hereditary atrial fibrillation

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJA5	HGNC:4279	ENSG00000265107	P36382	Gap junction alpha-5 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJA5	Gap junction alpha-5 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJA5	Other/Unknown	no		Connexin, Connexin40, Connexin_N

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left coronary artery	1
placenta	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJA5	190	broad	marker	placenta, right coronary artery, left coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJA5	1,476

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJA5	P36382	70.35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gap junction assembly	1	292.8×	0.003	GJA5

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
mitral valve development	1	16852.0×	3e-04	GJA5
septum primum development	1	16852.0×	3e-04	GJA5
atrial ventricular junction remodeling	1	16852.0×	3e-04	GJA5
positive regulation of cell communication by chemical coupling	1	16852.0×	3e-04	GJA5
atrial cardiac muscle cell to AV node cell communication by electrical coupling	1	16852.0×	3e-04	GJA5
Purkinje myocyte to ventricular cardiac muscle cell communication by electrical coupling	1	16852.0×	3e-04	GJA5
regulation of Purkinje myocyte action potential	1	16852.0×	3e-04	GJA5
regulation of renin secretion into blood stream	1	16852.0×	3e-04	GJA5
vasomotion	1	16852.0×	3e-04	GJA5
pulmonary valve formation	1	8426.0×	4e-04	GJA5
cell communication by chemical coupling	1	8426.0×	4e-04	GJA5
foramen ovale closure	1	8426.0×	4e-04	GJA5
SA node cell to atrial cardiac muscle cell communication by electrical coupling	1	8426.0×	4e-04	GJA5
AV node cell to bundle of His cell communication by electrical coupling	1	8426.0×	4e-04	GJA5
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	8426.0×	4e-04	GJA5
regulation of bundle of His cell action potential	1	8426.0×	4e-04	GJA5
regulation of AV node cell action potential	1	5617.3×	5e-04	GJA5
regulation of atrial cardiac muscle cell action potential	1	5617.3×	5e-04	GJA5
negative regulation of glomerular filtration	1	4213.0×	6e-04	GJA5
regulation of membrane depolarization during cardiac muscle cell action potential	1	4213.0×	6e-04	GJA5
regulation of ventricular cardiac muscle cell membrane depolarization	1	2808.7×	8e-04	GJA5
SA node cell action potential	1	2808.7×	8e-04	GJA5
regulation of cell communication by electrical coupling	1	2407.4×	9e-04	GJA5
atrial septum development	1	2106.5×	9e-04	GJA5
gap junction assembly	1	2106.5×	9e-04	GJA5
regulation of atrial cardiac muscle cell membrane depolarization	1	1872.4×	1e-03	GJA5
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.001	GJA5
endothelium development	1	1296.3×	0.001	GJA5
atrial septum morphogenesis	1	1296.3×	0.001	GJA5
cardiac conduction system development	1	1053.2×	0.002	GJA5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJA5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	GJA5

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)
GJA5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.