Surfactant metabolism dysfunction, pulmonary, 4

Summary

Surfactant metabolism dysfunction, pulmonary, 4 (MONDO:0010424) is a disease caused by CSF2RA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CSF2RA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 375

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	surfactant metabolism dysfunction, pulmonary, 4
Mondo ID	MONDO:0010424
MeSH	C567461
OMIM	300770
UMLS	C2677877
MedGen	393858
GARD	0015263
Is cancer (heuristic)	no

Also known as: SMDP4 · surfactant metabolism dysfunction, pulmonary, 4 · surfactant metabolism dysfunction, pulmonary, type 4

Data availability: 375 ClinVar variants · 2 GenCC gene-disease records.

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, 4

Related subtypes (7): surfactant metabolism dysfunction, pulmonary, 1, 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

375 retrieved; paginated sample, class counts are floors:

179 likely benign, 142 uncertain significance, 19 benign, 18 pathogenic, 6 likely pathogenic, 6 benign/likely benign, 4 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10355	NM_172245.4(CSF2RA):c.586G>A (p.Gly196Arg)	CSF2RA	Pathogenic	criteria provided, single submitter
1070210	NM_172245.4(CSF2RA):c.140dup (p.Leu47fs)	CSF2RA	Pathogenic	criteria provided, single submitter
1074981	NM_172245.4(CSF2RA):c.82C>T (p.Arg28Ter)	CSF2RA	Pathogenic	criteria provided, single submitter
1075180	NM_172245.4(CSF2RA):c.547del (p.Leu183fs)	CSF2RA	Pathogenic	criteria provided, single submitter
1362907	NM_172245.4(CSF2RA):c.787C>T (p.Gln263Ter)	CSF2RA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1433550	NM_172245.4(CSF2RA):c.917G>A (p.Trp306Ter)	CSF2RA	Pathogenic	criteria provided, single submitter
1451266	NM_172245.4(CSF2RA):c.414G>A (p.Trp138Ter)	CSF2RA	Pathogenic	criteria provided, single submitter
1685678	NM_172245.4(CSF2RA):c.649C>T (p.Arg217Ter)	CSF2RA	Pathogenic	criteria provided, single submitter
1685679	NM_172245.4(CSF2RA):c.920_921dup (p.Ser308fs)	CSF2RA	Pathogenic	criteria provided, single submitter
2062607	NM_172245.4(CSF2RA):c.341C>G (p.Ser114Ter)	CSF2RA	Pathogenic	criteria provided, single submitter
2088110	NM_172245.4(CSF2RA):c.350_353del (p.Glu117fs)	CSF2RA	Pathogenic	criteria provided, single submitter
2785274	NM_172245.4(CSF2RA):c.669dup (p.Val224fs)	CSF2RA	Pathogenic	criteria provided, single submitter
2805729	NM_172245.4(CSF2RA):c.147G>A (p.Trp49Ter)	CSF2RA	Pathogenic	criteria provided, single submitter
2817095	NM_172245.4(CSF2RA):c.865del (p.Arg289fs)	CSF2RA	Pathogenic	criteria provided, single submitter
3689735	NM_172245.4(CSF2RA):c.221del (p.Leu74fs)	CSF2RA	Pathogenic	criteria provided, single submitter
839421	NM_172245.4(CSF2RA):c.368_377del (p.Asn123fs)	CSF2RA	Pathogenic	criteria provided, single submitter
847249	NM_172245.4(CSF2RA):c.610C>T (p.Gln204Ter)	CSF2RA	Pathogenic	criteria provided, multiple submitters, no conflicts
856809	NM_172245.4(CSF2RA):c.595C>T (p.Arg199Ter)	CSF2RA	Pathogenic	criteria provided, multiple submitters, no conflicts
10354	NG_012280.1:g.(22122_24720)(45680?)del	MIR3690	Pathogenic	no assertion criteria provided
1473649	NM_172245.4(CSF2RA):c.810+2T>A	CSF2RA	Likely pathogenic	criteria provided, single submitter
1948181	NM_172245.4(CSF2RA):c.647-2A>G	CSF2RA	Likely pathogenic	criteria provided, single submitter
1973069	NM_172245.4(CSF2RA):c.586G>C (p.Gly196Arg)	CSF2RA	Likely pathogenic	criteria provided, single submitter
2189920	NM_172245.4(CSF2RA):c.1043+1G>A	CSF2RA	Likely pathogenic	criteria provided, single submitter
4820183	NC_000023.10:g.1393559_1448559del	CSF2RA	Likely pathogenic	criteria provided, single submitter
4849453	NM_172245.4(CSF2RA):c.220-1G>C	CSF2RA	Likely pathogenic	criteria provided, single submitter
1012852	NM_172245.4(CSF2RA):c.689C>T (p.Thr230Met)	CSF2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193687	NM_172245.4(CSF2RA):c.921C>T (p.Ser307=)	CSF2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
642779	NM_172245.4(CSF2RA):c.251G>A (p.Arg84His)	CSF2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
643235	NM_172245.4(CSF2RA):c.530G>C (p.Gly177Ala)	CSF2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009889	NM_172245.4(CSF2RA):c.442G>A (p.Val148Ile)	CSF2RA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
CSF2RA	Definitive	Autosomal recessive	surfactant metabolism dysfunction, pulmonary, 4	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSF2RA	Orphanet:264675	Hereditary pulmonary alveolar proteinosis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CSF2RA	HGNC:2435	ENSG00000198223	P15509	Granulocyte-macrophage colony-stimulating factor receptor subunit alpha	gencc,clinvar
MIR3690	HGNC:38967			microRNA 3690	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSF2RA	Granulocyte-macrophage colony-stimulating factor receptor subunit alpha	Low affinity receptor for granulocyte-macrophage colony-stimulating factor.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CSF2RA	Antibody/Immunoglobulin	yes		Short_hematopoietin_rcpt_2_CS, FN3_dom, Ig-like_fold
MIR3690	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

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	1

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSF2RA	193		marker	monocyte, mononuclear cell, leukocyte
MIR3690

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSF2RA	1,335
MIR3690	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSF2RA	P15509	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Defective CSF2RB causes SMDP5	1	1631.4×	0.002	CSF2RA
Defective CSF2RA causes SMDP4	1	1631.4×	0.002	CSF2RA
Interleukin receptor SHC signaling	1	407.9×	0.004	CSF2RA
Surfactant metabolism	1	368.4×	0.004	CSF2RA
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	317.2×	0.004	CSF2RA
RAF/MAP kinase cascade	1	61.1×	0.016	CSF2RA

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
granulocyte-macrophage colony-stimulating factor signaling pathway	1	4213.0×	0.001	CSF2RA
positive regulation of leukocyte proliferation	1	2808.7×	0.001	CSF2RA
growth hormone receptor signaling pathway	1	1203.7×	0.002	CSF2RA
positive regulation of receptor signaling pathway via JAK-STAT	1	432.1×	0.004	CSF2RA
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.005	CSF2RA
cytokine-mediated signaling pathway	1	130.6×	0.009	CSF2RA
positive regulation of cell population proliferation	1	33.6×	0.030	CSF2RA

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
CSF2RA	0	0
MIR3690	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	1	CSF2RA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MIR3690

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)
CSF2RA	0	—
MIR3690	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.