Surfactant metabolism dysfunction, pulmonary, 1

Summary

Surfactant metabolism dysfunction, pulmonary, 1 (MONDO:0009929) is a disease caused by SFTPB (GenCC Strong), with 3 cohort genes. The dominant Reactome pathway is Surfactant metabolism (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SFTPB (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 92
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	<1 / 1 000 000	0.067	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0002643	Neonatal respiratory distress	Very frequent (80-99%)
HP:0002789	Tachypnea	Very frequent (80-99%)
HP:0006517	Intraalveolar phospholipid accumulation	Very frequent (80-99%)
HP:0006530	Abnormal pulmonary interstitial morphology	Very frequent (80-99%)
HP:0002092	Pulmonary arterial hypertension	Frequent (30-79%)
HP:0002113	Pulmonary infiltrates	Frequent (30-79%)
HP:0031457	Pulmonary opacity	Frequent (30-79%)
HP:0001667	Right ventricular hypertrophy	Occasional (5-29%)
HP:0004876	Spontaneous neonatal pneumothorax	Occasional (5-29%)
HP:0006515	Interstitial pneumonitis	Occasional (5-29%)
HP:0006528	Chronic lung disease	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	surfactant metabolism dysfunction, pulmonary, 1
Mondo ID	MONDO:0009929
MeSH	C566882
OMIM	265120
Orphanet	217563
UMLS	C1968602
MedGen	368844
GARD	0017126
Is cancer (heuristic)	no

Also known as: interstitial lung disease due to SP-B dysfunction · interstitial lung disease due to surfactant Protein B deficiency · neonatal acute respiratory distress due to SP-B deficiency · neonatal acute respiratory distress due to surfactant protein B deficiency · pulmonary alveolar proteinosis, congenital, 1 · pulmonary surfactant protein B, deficiency of · SMDP1 · surfactant metabolism dysfunction, pulmonary, 1 · surfactant metabolism dysfunction, pulmonary, type 1

Data availability: 92 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

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 › surfactant metabolism dysfunction, pulmonary, 1

Related subtypes (7): surfactant metabolism dysfunction, pulmonary, 4, interstitial lung disease due to ABCA3 deficiency, 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

92 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 15 conflicting classifications of pathogenicity, 12 benign, 8 likely benign, 7 benign/likely benign, 6 pathogenic, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1520597	NM_001089.3(ABCA3):c.622C>T (p.Arg208Trp)	ABCA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13201	NM_000542.5(SFTPB):c.361delinsGAA (p.Pro121fs)	SFTPB	Pathogenic	criteria provided, multiple submitters, no conflicts
13202	NM_000542.5(SFTPB):c.365del (p.Leu122fs)	SFTPB	Pathogenic	criteria provided, single submitter
13203	SFTPB, 1-BP DEL, 457C	SFTPB	Pathogenic	no assertion criteria provided
13205	NM_000542.5(SFTPB):c.465G>T (p.Gly155=)	SFTPB	Pathogenic	no assertion criteria provided
587605	NM_000542.5(SFTPB):c.1084-1G>A	SFTPB	Pathogenic	criteria provided, single submitter
631868	NM_000542.5(SFTPB):c.361_362insAA (p.Pro121fs)	SFTPB	Pathogenic	criteria provided, multiple submitters, no conflicts
2433325	NM_000542.5(SFTPB):c.479del (p.Leu160fs)	SFTPB	Likely pathogenic	criteria provided, single submitter
2627672	NM_000542.5(SFTPB):c.324dup (p.Met109fs)	SFTPB	Likely pathogenic	criteria provided, single submitter
4280031	NM_000542.5(SFTPB):c.439C>T (p.Gln147Ter)	SFTPB	Likely pathogenic	criteria provided, single submitter
978726	NM_000542.5(SFTPB):c.730G>A (p.Gly244Ser)	SFTPB	Likely pathogenic	criteria provided, single submitter
1030864	NM_000542.5(SFTPB):c.673-14C>A	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13204	NM_000542.5(SFTPB):c.706C>T (p.Arg236Cys)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3340715	NM_000542.5(SFTPB):c.1029_1031dup (p.Pro344_Gln345insPro)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337304	NM_000542.5(SFTPB):c.780G>A (p.Thr260=)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337307	NM_000542.5(SFTPB):c.583-15T>C	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337308	NM_000542.5(SFTPB):c.570G>C (p.Gly190=)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337309	NM_000542.5(SFTPB):c.560C>T (p.Ala187Val)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337310	NM_000542.5(SFTPB):c.546C>T (p.Pro182=)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337314	NM_198843.4(SFTPB):c.-31C>T	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
593184	NM_000542.5(SFTPB):c.403G>A (p.Gly135Ser)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721228	NM_000542.5(SFTPB):c.190G>A (p.Gly64Arg)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895246	NM_000542.5(SFTPB):c.547G>A (p.Gly183Arg)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896677	NM_000542.5(SFTPB):c.361C>G (p.Pro121Ala)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896680	NM_000542.5(SFTPB):c.225C>T (p.Ile75=)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898229	NM_000542.5(SFTPB):c.725C>T (p.Ala242Val)	SFTPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587503	NM_001089.3(ABCA3):c.1225C>G (p.Leu409Val)	ABCA3	Uncertain significance	criteria provided, single submitter
1775459	NM_000542.5(SFTPB):c.1010A>T (p.Gln337Leu)	SFTPB	Uncertain significance	criteria provided, multiple submitters, no conflicts
178807	NM_000542.5(SFTPB):c.548G>A (p.Gly183Glu)	SFTPB	Uncertain significance	criteria provided, multiple submitters, no conflicts
198927	NM_000542.5(SFTPB):c.826C>T (p.Arg276Trp)	SFTPB	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 10 · 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
SFTPB	Strong	Autosomal recessive	surfactant metabolism dysfunction, pulmonary, 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SFTPB	Orphanet:217563	Neonatal acute respiratory distress syndrome
SFTPB	Orphanet:685082	Pediatric acute respiratory distress syndrome
SFTPC	Orphanet:2032	Idiopathic pulmonary fibrosis
SFTPC	Orphanet:217566	Chronic respiratory distress with surfactant metabolism deficiency
SFTPC	Orphanet:440392	Interstitial lung disease due to SP-C deficiency
SFTPC	Orphanet:685082	Pediatric acute respiratory distress syndrome
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

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SFTPB	HGNC:10801	ENSG00000168878	P07988	Pulmonary surfactant-associated protein B	gencc,clinvar
SFTPC	HGNC:10802	ENSG00000168484	P11686	Surfactant protein C	clinvar
ABCA3	HGNC:33	ENSG00000167972	Q99758	Phospholipid-transporting ATPase ABCA3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SFTPB	Pulmonary surfactant-associated protein B	Pulmonary surfactant-associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.
SFTPC	Surfactant protein C	Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.
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…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	25.9×	0.076
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SFTPB	Other/Unknown	no		SAP_A, SapB_1, SapB_2
SFTPC	Other/Unknown	no		SP-C, BRICHOS_dom, Surfactant_protein_propep
ABCA3	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower lobe of lung	3
upper lobe of lung	2
visceral pleura	1
adult organism	1
right lung	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SFTPB	231	tissue_specific	marker	lower lobe of lung, visceral pleura, upper lobe of lung
SFTPC	208	tissue_specific	marker	lower lobe of lung, right lung, adult organism
ABCA3	222	ubiquitous	marker	lower lobe of lung, upper lobe of lung, upper lobe of left lung

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SFTPC	1,613
ABCA3	1,436
SFTPB	899

Intra-cohort edges

A	B	Sources
ABCA3	SFTPB	string_interaction
ABCA3	SFTPC	string_interaction
SFTPB	SFTPC	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SFTPB	P07988	9
SFTPC	P11686	3
ABCA3	Q99758	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Surfactant metabolism	3	368.4×	3e-07	SFTPB, SFTPC, ABCA3
Defective CSF2RB causes SMDP5	2	1087.6×	5e-06	SFTPB, SFTPC
Defective CSF2RA causes SMDP4	2	1087.6×	5e-06	SFTPB, SFTPC
Defective ABCA3 causes SMDP3	1	3806.7×	6e-04	ABCA3
Defective pro-SFTPB causes SMDP1 and RDS	1	3806.7×	6e-04	SFTPB
Defective pro-SFTPC causes SMDP2 and RDS	1	3806.7×	6e-04	SFTPC
Diseases associated with surfactant metabolism	1	951.7×	0.002	ABCA3
ABC transporters in lipid homeostasis	1	200.3×	0.009	ABCA3
ABC transporter disorders	1	146.4×	0.011	ABCA3
Disorders of transmembrane transporters	1	46.4×	0.031	ABCA3
ABC-family protein mediated transport	1	40.5×	0.033	ABCA3
Diseases of metabolism	1	26.8×	0.045	ABCA3
Transport of small molecules	1	8.4×	0.131	ABCA3
Disease	1	4.4×	0.223	ABCA3
Metabolism of proteins	1	4.1×	0.223	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
respiratory gaseous exchange by respiratory system	2	416.1×	2e-04	SFTPB, SFTPC
positive regulation of protein homooligomerization	1	5617.3×	0.002	ABCA3
regulation of phosphatidylcholine metabolic process	1	2808.7×	0.003	ABCA3
xenobiotic export from cell	1	1872.4×	0.003	ABCA3
positive regulation of phospholipid efflux	1	1404.3×	0.003	ABCA3
regulation of lipid biosynthetic process	1	936.2×	0.003	ABCA3
organelle assembly	1	936.2×	0.003	ABCA3
positive regulation of phospholipid transport	1	802.5×	0.003	ABCA3
phosphatidylglycerol metabolic process	1	468.1×	0.005	ABCA3
sphingolipid metabolic process	1	330.4×	0.005	SFTPB
phospholipid homeostasis	1	330.4×	0.005	ABCA3
xenobiotic transmembrane transport	1	312.1×	0.005	ABCA3
xenobiotic transport	1	280.9×	0.005	ABCA3
surfactant homeostasis	1	267.5×	0.005	ABCA3
phosphatidylcholine metabolic process	1	267.5×	0.005	ABCA3
phospholipid transport	1	234.1×	0.006	ABCA3
positive regulation of cholesterol efflux	1	208.1×	0.006	ABCA3
response to glucocorticoid	1	108.0×	0.011	ABCA3
lipid transport	1	87.8×	0.013	ABCA3
lung development	1	66.1×	0.016	ABCA3
animal organ morphogenesis	1	63.8×	0.016	SFTPB
response to xenobiotic stimulus	1	23.0×	0.043	ABCA3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
SFTPB	0	0
SFTPC	0	0
ABCA3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	SFTPB, SFTPC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SFTPB	0	—
SFTPC	0	—
ABCA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.