Ventricular septal defect 3

Summary

Ventricular septal defect 3 (MONDO:0013749) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 45

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ventricular septal defect 3
Mondo ID	MONDO:0013749
OMIM	614432
UMLS	C3280785
MedGen	482415
Is cancer (heuristic)	no

Also known as: NKX2-5 ventricular septal defect (disease) · ventricular septal defect (disease) caused by mutation in NKX2-5 · ventricular septal defect 3 · ventricular septal defect type 3 · VSD3

Data availability: 45 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 › ventricular septal defect › ventricular septal defect 3

Related subtypes (4): ventricular septal defect 1, ventricular septal defect 2, double outlet right ventricle, anterior deviation infundibular septum

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

45 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 11 conflicting classifications of pathogenicity, 4 likely benign, 1 pathogenic/likely pathogenic, 1 benign/likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
159257	NM_004387.4(NKX2-5):c.783del (p.Ala262fs)	NKX2-5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30116	NM_004387.4(NKX2-5):c.175C>G (p.Pro59Ala)	NKX2-5	Pathogenic	no assertion criteria provided
4277239	NM_004387.4(NKX2-5):c.545T>C (p.Val182Ala)	NKX2-5	Likely pathogenic	criteria provided, single submitter
1019319	NM_004387.4(NKX2-5):c.178G>C (p.Glu60Gln)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021433	NM_004387.4(NKX2-5):c.169G>T (p.Ala57Ser)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1377875	NM_004387.4(NKX2-5):c.510G>C (p.Gln170His)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1439076	NM_004387.4(NKX2-5):c.370A>G (p.Lys124Glu)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156161	NM_004387.4(NKX2-5):c.809G>A (p.Cys270Tyr)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709619	NM_004387.4(NKX2-5):c.737A>G (p.Asn246Ser)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372743	NM_004387.4(NKX2-5):c.356C>A (p.Ala119Glu)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392351	NM_004387.4(NKX2-5):c.827C>G (p.Ala276Gly)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
505440	NM_004387.4(NKX2-5):c.111G>A (p.Leu37=)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
850796	NM_004387.4(NKX2-5):c.188C>T (p.Ala63Val)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
939551	NM_004387.4(NKX2-5):c.387C>A (p.Asn129Lys)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016187	NM_004387.4(NKX2-5):c.650G>A (p.Arg217Lys)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021042	NM_004387.4(NKX2-5):c.521T>G (p.Val174Gly)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022958	NM_004387.4(NKX2-5):c.248C>G (p.Ala83Gly)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061973	NM_004387.4(NKX2-5):c.627GCC[7] (p.Pro213_Pro214dup)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1308506	NM_004387.4(NKX2-5):c.893G>A (p.Gly298Glu)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1437112	NM_004387.4(NKX2-5):c.494C>T (p.Ala165Val)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1513563	NM_004387.4(NKX2-5):c.763G>A (p.Ala255Thr)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1705341	NM_004387.4(NKX2-5):c.547A>C (p.Lys183Gln)	NKX2-5	Uncertain significance	criteria provided, single submitter
190835	NM_004387.4(NKX2-5):c.590G>C (p.Arg197Pro)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
283727	NM_004387.4(NKX2-5):c.769C>A (p.Pro257Thr)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
30115	NM_004387.4(NKX2-5):c.848C>A (p.Pro283Gln)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
30117	NM_004387.4(NKX2-5):c.769C>G (p.Pro257Ala)	NKX2-5	Uncertain significance	criteria provided, single submitter
410967	NM_004387.4(NKX2-5):c.824C>T (p.Pro275Leu)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
410969	NM_004387.4(NKX2-5):c.865AAC[2] (p.Asn291del)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
453141	NM_004387.4(NKX2-5):c.886G>A (p.Gly296Ser)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
468245	NM_004387.4(NKX2-5):c.65A>C (p.Gln22Pro)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-5	Orphanet:101351	Familial isolated congenital asplenia
NKX2-5	Orphanet:1479	Atrial septal defect-atrioventricular conduction defects syndrome
NKX2-5	Orphanet:1627	Deletion 5q35 syndrome
NKX2-5	Orphanet:2248	Hypoplastic left heart syndrome
NKX2-5	Orphanet:3303	Tetralogy of Fallot
NKX2-5	Orphanet:334	Hereditary atrial fibrillation
NKX2-5	Orphanet:402075	Familial bicuspid aortic valve
NKX2-5	Orphanet:871	Hereditary progressive cardiac conduction defect
NKX2-5	Orphanet:95712	Thyroid ectopia
NKX2-5	Orphanet:95713	Athyreosis
NKX2-5	Orphanet:99103	Atrial septal defect, ostium secundum type

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
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

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
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-5	2,355

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NKX2-5	P52952	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	761.3×	0.002	NKX2-5
Physiological factors	1	671.8×	0.002	NKX2-5
Cardiogenesis	1	423.0×	0.002	NKX2-5

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
Purkinje myocyte differentiation	1	16852.0×	0.001	NKX2-5
septum secundum development	1	16852.0×	0.001	NKX2-5
right ventricular cardiac muscle tissue morphogenesis	1	8426.0×	0.001	NKX2-5
atrioventricular node cell fate commitment	1	8426.0×	0.001	NKX2-5
cardiac ventricle formation	1	5617.3×	0.001	NKX2-5
apoptotic process involved in heart morphogenesis	1	5617.3×	0.001	NKX2-5
proepicardium development	1	5617.3×	0.001	NKX2-5
pulmonary myocardium development	1	5617.3×	0.001	NKX2-5
ventricular cardiac myofibril assembly	1	5617.3×	0.001	NKX2-5
atrial cardiac muscle cell development	1	5617.3×	0.001	NKX2-5
bundle of His development	1	4213.0×	0.001	NKX2-5
atrial cardiac muscle tissue development	1	4213.0×	0.001	NKX2-5
positive regulation of cardioblast differentiation	1	4213.0×	0.001	NKX2-5
atrioventricular node cell development	1	4213.0×	0.001	NKX2-5
regulation of cardiac muscle cell proliferation	1	3370.4×	0.001	NKX2-5
atrioventricular node development	1	2808.7×	0.001	NKX2-5
embryonic heart tube left/right pattern formation	1	2808.7×	0.001	NKX2-5
positive regulation of heart contraction	1	2106.5×	0.002	NKX2-5
ventricular cardiac muscle cell development	1	1532.0×	0.002	NKX2-5
cardiac muscle tissue morphogenesis	1	1404.3×	0.002	NKX2-5
atrial septum morphogenesis	1	1296.3×	0.002	NKX2-5
adult heart development	1	1203.7×	0.002	NKX2-5
cardiac septum morphogenesis	1	1203.7×	0.002	NKX2-5
negative regulation of epithelial cell apoptotic process	1	1203.7×	0.002	NKX2-5
negative regulation of myotube differentiation	1	1123.5×	0.002	NKX2-5
heart trabecula formation	1	1123.5×	0.002	NKX2-5
cardiac conduction system development	1	1053.2×	0.002	NKX2-5
ventricular trabecula myocardium morphogenesis	1	1053.2×	0.002	NKX2-5
regulation of cardiac muscle contraction	1	887.0×	0.002	NKX2-5
positive regulation of sodium ion transport	1	842.6×	0.002	NKX2-5

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
NKX2-5	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	NKX2-5

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)
NKX2-5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.