interstitial lung disease due to ABCA3 deficiency

Summary

interstitial lung disease due to ABCA3 deficiency (MONDO:0012582) is a disease caused by ABCA3 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ABCA3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 338

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	interstitial lung disease due to ABCA3 deficiency
Mondo ID	MONDO:0012582
MeSH	C567046
OMIM	610921
Orphanet	440402
UMLS	C1970456
MedGen	410074
GARD	0017745
Is cancer (heuristic)	no

Also known as: interstitial lung disease due to ABCA3 deficiency · interstitial lung disease due to ATP-binding cassette subfamily A member 3 deficiency · SMDP3 · surfactant metabolism dysfunction, pulmonary, 3 · surfactant metabolism dysfunction, pulmonary, type 3

Data availability: 338 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › pulmonary alveolar proteinosis › hereditary pulmonary alveolar proteinosis › interstitial lung disease due to ABCA3 deficiency

Related subtypes (7): surfactant metabolism dysfunction, pulmonary, 1, surfactant metabolism dysfunction, pulmonary, 4, surfactant metabolism dysfunction, pulmonary, 5, severe early-onset pulmonary alveolar proteinosis due to MARS deficiency, chronic respiratory distress with surfactant metabolism deficiency, SFTPC-related interstitial lung disease, surfactant metabolism dysfunction, pulmonary, 2

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

338 retrieved; paginated sample, class counts are floors:

126 uncertain significance, 93 conflicting classifications of pathogenicity, 36 likely pathogenic, 24 benign, 20 pathogenic, 15 pathogenic/likely pathogenic, 14 benign/likely benign, 10 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1211382	NM_001089.3(ABCA3):c.3863-98C>T	ABCA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1251986	NM_001089.3(ABCA3):c.3235C>T (p.Gln1079Ter)	ABCA3	Pathogenic	no assertion criteria provided
1322151	NM_001089.3(ABCA3):c.1286-2A>G	ABCA3	Pathogenic	criteria provided, single submitter
1331730	NM_001089.3(ABCA3):c.4141_4142del (p.Leu1381fs)	ABCA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1520597	NM_001089.3(ABCA3):c.622C>T (p.Arg208Trp)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1738591	NM_001089.3(ABCA3):c.4195G>A (p.Val1399Met)	ABCA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1740383	NM_001089.3(ABCA3):c.440C>T (p.Pro147Leu)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1758921	NM_001089.3(ABCA3):c.743C>T (p.Pro248Leu)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1767530	NM_001089.3(ABCA3):c.127C>T (p.Arg43Cys)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1773032	NM_001089.3(ABCA3):c.1455C>G (p.Tyr485Ter)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203381	NM_001089.3(ABCA3):c.875A>T (p.Glu292Val)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228321	NM_001089.3(ABCA3):c.128G>A (p.Arg43His)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577338	NM_001089.3(ABCA3):c.537G>C (p.Trp179Cys)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2581630	NM_001089.3(ABCA3):c.2741A>G (p.Lys914Arg)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736309	NM_001089.3(ABCA3):c.2890G>A (p.Gly964Ser)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736313	NM_001089.3(ABCA3):c.604G>A (p.Gly202Arg)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2862508	NM_001089.3(ABCA3):c.2188_2189dup (p.Asp731fs)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2910398	NM_001089.3(ABCA3):c.1303C>T (p.Arg435Ter)	ABCA3	Pathogenic	criteria provided, multiple submitters, no conflicts
3233564	NM_001089.3(ABCA3):c.4090G>A (p.Glu1364Lys)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384191	NM_001089.3(ABCA3):c.1467+1903_1612-126del	ABCA3	Pathogenic	criteria provided, single submitter
3579944	NM_001089.3(ABCA3):c.4675C>T (p.Arg1559Ter)	ABCA3	Pathogenic	criteria provided, single submitter
3630012	NM_001089.3(ABCA3):c.4765C>T (p.Gln1589Ter)	ABCA3	Pathogenic	criteria provided, single submitter
4796623	NM_001089.3(ABCA3):c.494G>A (p.Trp165Ter)	ABCA3	Pathogenic	criteria provided, single submitter
619285	NM_001089.3(ABCA3):c.817_821del (p.Tyr273fs)	ABCA3	Pathogenic	criteria provided, multiple submitters, no conflicts
8011	NM_001089.3(ABCA3):c.3426G>A (p.Trp1142Ter)	ABCA3	Pathogenic	criteria provided, multiple submitters, no conflicts
8012	NM_001089.3(ABCA3):c.302T>C (p.Leu101Pro)	ABCA3	Pathogenic	no assertion criteria provided
8013	NM_001089.3(ABCA3):c.4658T>C (p.Leu1553Pro)	ABCA3	Pathogenic	no assertion criteria provided
8014	NM_001089.3(ABCA3):c.4772A>C (p.Gln1591Pro)	ABCA3	Pathogenic	no assertion criteria provided
8015	NM_001089.3(ABCA3):c.1702A>G (p.Asn568Asp)	ABCA3	Pathogenic	no assertion criteria provided
8016	NM_001089.3(ABCA3):c.4909+1G>A	ABCA3	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 8 · 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
ABCA3	Strong	Autosomal recessive	interstitial lung disease due to ABCA3 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCA3	Orphanet:2032	Idiopathic pulmonary fibrosis
ABCA3	Orphanet:217563	Neonatal acute respiratory distress syndrome
ABCA3	Orphanet:440402	Interstitial lung disease due to ABCA3 deficiency
ABCA3	Orphanet:685082	Pediatric acute respiratory distress syndrome
F8	Orphanet:169802	Severe hemophilia A
F8	Orphanet:169805	Moderate hemophilia A
F8	Orphanet:169808	Mild hemophilia A
F8	Orphanet:177926	Bleeding disorder in hemophilia A carriers

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
ABCA3	HGNC:33	ENSG00000167972	Q99758	Phospholipid-transporting ATPase ABCA3	gencc,clinvar
F8	HGNC:3546	ENSG00000185010	P00451	Coagulation factor VIII	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCA3	Phospholipid-transporting ATPase ABCA3	Catalyzes the ATP-dependent transport of phospholipids such as phosphatidylcholine and phosphoglycerol from the cytoplasm into the lumen side of lamellar bodies, in turn participates in the lamellar bodies biogenesis and homeostasis of pul…
F8	Coagulation factor VIII	Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.

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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCA3	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
F8	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf

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
lower lobe of lung	1
upper lobe of left lung	1
upper lobe of lung	1
heart right ventricle	1
left ventricle myocardium	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCA3	222	ubiquitous	marker	lower lobe of lung, upper lobe of lung, upper lobe of left lung
F8	266	broad	marker	left ventricle myocardium, heart right ventricle, myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F8	1,900
ABCA3	1,436

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F8	P00451	25
ABCA3	Q99758	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. 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
Defective ABCA3 causes SMDP3	1	5710.0×	1e-03	ABCA3
Defective F8 accelerates dissociation of the A2 domain	1	5710.0×	1e-03	F8
Defective F8 binding to the cell membrane	1	5710.0×	1e-03	F8
Defective F8 secretion	1	5710.0×	1e-03	F8
Defective F8 binding to von Willebrand factor	1	2855.0×	0.001	F8
Defective factor IX causes thrombophilia	1	1903.3×	0.001	F8
Defective F8 cleavage by thrombin	1	1903.3×	0.001	F8
Defective cofactor function of FVIIIa variant	1	1903.3×	0.001	F8
Defective F9 variant does not activate FX	1	1903.3×	0.001	F8
Defective F8 sulfation at Y1699	1	1903.3×	0.001	F8
Diseases associated with surfactant metabolism	1	1427.5×	0.002	ABCA3
Amplification and propagation of coagulation cascade	1	317.2×	0.007	F8
ABC transporters in lipid homeostasis	1	300.5×	0.007	ABCA3
Initiation of coagulation cascade	1	237.9×	0.008	F8
ABC transporter disorders	1	219.6×	0.008	ABCA3
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	211.5×	0.008	F8
Surfactant metabolism	1	184.2×	0.008	ABCA3
Cargo concentration in the ER	1	167.9×	0.009	F8
Regulation of clotting cascade	1	116.5×	0.012	F8
COPII-mediated vesicle transport	1	81.6×	0.016	F8
Disorders of transmembrane transporters	1	69.6×	0.018	ABCA3
ABC-family protein mediated transport	1	60.7×	0.020	ABCA3
Platelet degranulation	1	43.9×	0.026	F8
Diseases of metabolism	1	40.2×	0.028	ABCA3
Transport of small molecules	1	12.6×	0.084	ABCA3
Disease	1	6.5×	0.152	ABCA3
Metabolism of proteins	1	6.2×	0.155	ABCA3

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
positive regulation of protein homooligomerization	1	8426.0×	0.003	ABCA3
regulation of phosphatidylcholine metabolic process	1	4213.0×	0.003	ABCA3
xenobiotic export from cell	1	2808.7×	0.003	ABCA3
positive regulation of phospholipid efflux	1	2106.5×	0.003	ABCA3
regulation of lipid biosynthetic process	1	1404.3×	0.003	ABCA3
organelle assembly	1	1404.3×	0.003	ABCA3
positive regulation of phospholipid transport	1	1203.7×	0.003	ABCA3
blood coagulation, intrinsic pathway	1	1053.2×	0.003	F8
phosphatidylglycerol metabolic process	1	702.2×	0.003	ABCA3
phospholipid homeostasis	1	495.6×	0.004	ABCA3
xenobiotic transmembrane transport	1	468.1×	0.004	ABCA3
xenobiotic transport	1	421.3×	0.004	ABCA3
surfactant homeostasis	1	401.2×	0.004	ABCA3
phosphatidylcholine metabolic process	1	401.2×	0.004	ABCA3
phospholipid transport	1	351.1×	0.004	ABCA3
positive regulation of cholesterol efflux	1	312.1×	0.004	ABCA3
acute-phase response	1	210.7×	0.006	F8
response to glucocorticoid	1	162.0×	0.008	ABCA3
lipid transport	1	131.7×	0.009	ABCA3
lung development	1	99.1×	0.011	ABCA3
blood coagulation	1	86.9×	0.012	F8
response to xenobiotic stimulus	1	34.5×	0.029	ABCA3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCA3	0	0
F8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
F8	8	Binding:8

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

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	1	ABCA3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	F8

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCA3	0	—
F8	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.