Atrioventricular septal defect 4

Summary

Atrioventricular septal defect 4 (MONDO:0013747) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 786

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrioventricular septal defect 4
Mondo ID	MONDO:0013747
OMIM	614430
UMLS	C3280781
MedGen	482411
GARD	0024944
Is cancer (heuristic)	no

Also known as: atrioventricular septal defect 4 · atrioventricular septal defect caused by mutation in GATA4 · atrioventricular septal defect type 4 · AVSD4 · GATA4 atrioventricular septal defect

Data availability: 786 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › familial atrioventricular septal defect › atrioventricular septal defect 4

Related subtypes (5): atrioventricular septal defect 5, congenital heart defects, multiple types, 4, complete atrioventricular canal, partial atrioventricular canal, atrioventricular septal defect

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

600 retrieved; paginated sample, class counts are floors:

314 uncertain significance, 227 likely benign, 20 benign/likely benign, 14 conflicting classifications of pathogenicity, 12 pathogenic, 9 benign, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029405	NM_001308093.3(GATA4):c.851G>A (p.Arg284His)	GATA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361119	NM_001308093.3(GATA4):c.54C>A (p.Tyr18Ter)	GATA4	Pathogenic	criteria provided, single submitter
1452170	NM_001308093.3(GATA4):c.54C>G (p.Tyr18Ter)	GATA4	Pathogenic	criteria provided, single submitter
1458733	NM_001308093.3(GATA4):c.854G>A (p.Arg285His)	GATA4	Pathogenic	criteria provided, single submitter
1459470	NM_001308093.3(GATA4):c.266G>A (p.Trp89Ter)	GATA4	Pathogenic	criteria provided, single submitter
2424349	NC_000008.10:g.(?11565822)(11566457_?)del	GATA4	Pathogenic	criteria provided, single submitter
2711491	NM_001308093.3(GATA4):c.409G>T (p.Gly137Ter)	GATA4	Pathogenic	criteria provided, single submitter
2752218	NM_001308093.3(GATA4):c.923C>G (p.Pro308Arg)	GATA4	Pathogenic	criteria provided, single submitter
2812933	NM_001308093.3(GATA4):c.655_656del (p.Val219fs)	GATA4	Pathogenic	criteria provided, single submitter
2820525	NM_001308093.3(GATA4):c.887G>C (p.Cys296Ser)	GATA4	Pathogenic	criteria provided, single submitter
3245522	NC_000008.10:g.(?11565822)(11615984_?)del	GATA4	Pathogenic	criteria provided, single submitter
3631539	NM_001308093.3(GATA4):c.686G>A (p.Trp229Ter)	GATA4	Pathogenic	criteria provided, single submitter
4723478	NM_001308093.3(GATA4):c.947_957del (p.Ile316fs)	GATA4	Pathogenic	criteria provided, single submitter
1473702	NM_001308093.3(GATA4):c.879C>G (p.Cys293Trp)	GATA4	Likely pathogenic	criteria provided, single submitter
2967408	NM_001308093.3(GATA4):c.191G>A (p.Gly64Glu)	GATA4	Likely pathogenic	criteria provided, single submitter
4294343	NM_001308093.3(GATA4):c.920G>C (p.Arg307Thr)	GATA4	Likely pathogenic	criteria provided, single submitter
1200120	NM_001308093.3(GATA4):c.400A>T (p.Ser134Cys)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1410211	NM_001308093.3(GATA4):c.333G>A (p.Pro111=)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1431327	NM_001308093.3(GATA4):c.962G>A (p.Arg321Gln)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1470106	NM_001308093.3(GATA4):c.867C>T (p.Gly289=)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1483194	NM_001308093.3(GATA4):c.1241C>T (p.Pro414Leu)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1764007	NM_001308093.3(GATA4):c.85G>A (p.Gly29Ser)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2157839	NM_001308093.3(GATA4):c.615C>T (p.Leu205=)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30099	NM_001308093.3(GATA4):c.487C>T (p.Pro163Ser)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30101	NM_001308093.3(GATA4):c.1078G>A (p.Glu360Lys)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30103	NM_001308093.3(GATA4):c.1223C>A (p.Pro408Gln)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30104	NM_001308093.3(GATA4):c.357CGC[5] (p.Ala126dup)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3635303	NM_001308093.3(GATA4):c.1012_1014del (p.Ser338del)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44334	NM_001308093.3(GATA4):c.1132A>G (p.Ser378Gly)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44336	NM_001308093.3(GATA4):c.825C>T (p.Cys275=)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BLK	Orphanet:536	Systemic lupus erythematosus
BLK	Orphanet:552	MODY
GATA4	Orphanet:251071	8p23.1 microdeletion syndrome
GATA4	Orphanet:251510	46,XY partial gonadal dysgenesis
GATA4	Orphanet:3303	Tetralogy of Fallot
GATA4	Orphanet:334	Hereditary atrial fibrillation
GATA4	Orphanet:576232	Partial atrioventricular septal defect with ventricular hypoplasia
GATA4	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
GATA4	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
GATA4	Orphanet:99103	Atrial septal defect, ostium secundum type

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BLK	HGNC:1057	ENSG00000136573	P51451	Tyrosine-protein kinase Blk	clinvar
GATA4	HGNC:4173	ENSG00000136574	P43694	Transcription factor GATA-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BLK	Tyrosine-protein kinase Blk	Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling.
GATA4	Transcription factor GATA-4	Transcriptional activator that binds to the consensus sequence 5’-AGATAG-3’ and plays a key role in cardiac development and function.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BLK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
GATA4	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
lymph node	1
male germ line stem cell (sensu Vertebrata) in testis	1
spleen	1
duodenum	1
heart left ventricle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BLK	145	tissue_specific	marker	spleen, male germ line stem cell (sensu Vertebrata) in testis, lymph node
GATA4	85	broad	marker	right atrium auricular region, heart left ventricle, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA4	4,994
BLK	2,967

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GATA4	P43694	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BLK	P51451	81.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of lateral plate mesoderm	1	1142.0×	0.008	GATA4
RUNX1 regulates transcription of genes involved in BCR signaling	1	951.7×	0.008	BLK
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	439.2×	0.008	GATA4
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	380.7×	0.008	GATA4
Transcriptional regulation of testis differentiation	1	356.9×	0.008	GATA4
Formation of definitive endoderm	1	356.9×	0.008	GATA4
Physiological factors	1	335.9×	0.008	GATA4
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	300.5×	0.008	GATA4
Cardiogenesis	1	211.5×	0.010	GATA4
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.010	BLK
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.010	BLK
Developmental Lineage of Pancreatic Acinar Cells	1	150.3×	0.011	GATA4
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.013	GATA4
Transcriptional regulation by RUNX1	1	73.2×	0.019	BLK
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.040	GATA4
Adaptive Immune System	1	14.9×	0.082	BLK
RNA Polymerase II Transcription	1	11.3×	0.102	BLK
Gene expression (Transcription)	1	8.9×	0.121	BLK
Generic Transcription Pathway	1	7.5×	0.135	BLK
Immune System	1	6.5×	0.148	BLK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
atrial septum secundum morphogenesis	1	4213.0×	0.005	GATA4
embryonic heart tube anterior/posterior pattern specification	1	2808.7×	0.005	GATA4
atrioventricular valve formation	1	2106.5×	0.005	GATA4
cardiac muscle tissue regeneration	1	2106.5×	0.005	GATA4
atrial septum primum morphogenesis	1	1685.2×	0.005	GATA4
atrioventricular node development	1	1404.3×	0.005	GATA4
cell growth involved in cardiac muscle cell development	1	1203.7×	0.005	GATA4
transdifferentiation	1	1053.2×	0.005	GATA4
cardiac ventricle morphogenesis	1	936.2×	0.005	GATA4
embryonic foregut morphogenesis	1	842.6×	0.005	GATA4
atrioventricular canal development	1	766.0×	0.005	GATA4
intestinal epithelial cell differentiation	1	766.0×	0.005	GATA4
endocardial cushion development	1	702.2×	0.005	GATA4
cardiac right ventricle morphogenesis	1	702.2×	0.005	GATA4
atrial septum morphogenesis	1	648.1×	0.005	GATA4
regulation of cardiac muscle cell contraction	1	561.7×	0.005	GATA4
response to vitamin A	1	526.6×	0.005	GATA4
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	468.1×	0.005	GATA4
endoderm development	1	312.1×	0.008	GATA4
negative regulation of apoptotic signaling pathway	1	280.9×	0.008	GATA4
negative regulation of cardiac muscle cell apoptotic process	1	271.8×	0.008	GATA4
ventricular septum development	1	247.8×	0.008	GATA4
positive regulation of vascular endothelial growth factor production	1	247.8×	0.008	GATA4
positive regulation of BMP signaling pathway	1	227.7×	0.008	GATA4
aortic valve morphogenesis	1	216.1×	0.008	GATA4
peptidyl-tyrosine phosphorylation	1	210.7×	0.008	BLK
B cell receptor signaling pathway	1	200.6×	0.008	BLK
response to mechanical stimulus	1	150.5×	0.010	GATA4
cell fate commitment	1	147.8×	0.010	GATA4
heart looping	1	133.8×	0.011	GATA4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
BLK	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BLK	62	4
GATA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AFATINIB	4	BLK
FEDRATINIB	4	BLK
AXITINIB	4	BLK
SORAFENIB	4	BLK
NERATINIB	4	BLK
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK
BOSUTINIB	4	BLK
BRIGATINIB	4	BLK
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK
NINTEDANIB	4	BLK
SUNITINIB	4	BLK
DASATINIB	4	BLK
ERLOTINIB	4	BLK
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK
MIDOSTAURIN	4	BLK
GEFITINIB	4	BLK
IMATINIB	4	BLK
MASITINIB	3	BLK
LINIFANIB	3	BLK
CANERTINIB	3	BLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BLK	483	Binding:477, ADMET:4, Functional:2
GATA4	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BLK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BLK	483

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
AFATINIB	4	BLK
FEDRATINIB	4	BLK
AXITINIB	4	BLK
SORAFENIB	4	BLK
NERATINIB	4	BLK
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK
BOSUTINIB	4	BLK
BRIGATINIB	4	BLK
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK
NINTEDANIB	4	BLK
SUNITINIB	4	BLK
DASATINIB	4	BLK
ERLOTINIB	4	BLK
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK
MIDOSTAURIN	4	BLK
GEFITINIB	4	BLK
IMATINIB	4	BLK
MASITINIB	3	BLK
LINIFANIB	3	BLK
CANERTINIB	3	BLK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BLK
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	GATA4

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)
GATA4	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.