Pulmonary alveolar proteinosis

Summary

Pulmonary alveolar proteinosis (MONDO:0001437) is a disease with 1 cohort gene (2 GWAS associations across 1 studies) and 21 clinical trials. Top therapeutic interventions include rituximab, cyanocobalamin, and regramostim.

At a glance

• Cohort genes: 1
• GWAS associations: 2
• ClinVar variants: 3
• Clinical trials: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary alveolar proteinosis
Mondo ID	MONDO:0001437
MeSH	D011649
DOID	DOID:12120
ICD-11	1869739196
NCIT	C85037
SNOMED CT	10501004
UMLS	C5400698
MedGen	1763046
Is cancer (heuristic)	no

Also known as: PAP · pulmonary alveolar proteinosis

Data availability: 3 ClinVar variants · 2 GWAS associations (1 study).

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › pulmonary alveolar proteinosis

Related subtypes (32): aspiration pneumonia, lung abscess, pneumonic plague, pulmonary systemic sclerosis, obstructive lung disease, bronchiolitis, pulmonary immaturity, rheumatoid arthritis-associated interstitial lung disease, pulmonary embolism and infarction, acute chest syndrome, fungal lung infectious disease, middle lobe syndrome, pulmonary coin lesion, pulmonary plasma cell granuloma, silo filler disease, pulmonary alveolar microlithiasis, pulmonary venoocclusive disease, acute lung injury, interstitial lung disease, hantavirus pulmonary syndrome, pulmonary non-tuberculous mycobacterial infection, respiratory failure, lung neoplasm, occupational lung disease, Wilson-Mikity syndrome, neonatal aspiration syndrome, pneumonitis, vanishing lung syndrome, restrictive pulmonary disease, shrinking lung syndrome, dystrophic pulmonary ossification, pulmonary artery disease

Subtypes (3): autoimmune pulmonary alveolar proteinosis, hereditary pulmonary alveolar proteinosis, secondary pulmonary alveolar proteinosis

Genetics & variants

GWAS landscape

2 GWAS associations across 1 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs138024423	2e-12	HLA-DRB9 - HLA-DRB5	G	5.2
rs56125424	2e-07	RNA5SP173 - NDUFB5P1	?	3

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST012169	Sakaue S	2021	198	0	Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs138024423	6	32485494	GT>G	0.072	intron_variant	HLA-DRB9 - HLA-DRB5	2e-12	Tier 4: intronic/intergenic
rs56125424	4	179772417	A>G	0.11	intergenic_variant	RNA5SP173 - NDUFB5P1	2e-07	Tier 4: intronic/intergenic

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
189364	NM_004990.3(MARS):c.[1700C>T;1177G>A]		Pathogenic	no assertion criteria provided
424711	NM_004990.3(MARS1):c.[1031A>G];[1177G>A[1700C>T]		Pathogenic	no assertion criteria provided
189365	NM_004990.4(MARS1):c.1814A>T (p.Asp605Val)	MARS1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MARS1	Orphanet:397735	Autosomal dominant Charcot-Marie-Tooth disease type 2U
MARS1	Orphanet:401835	Autosomal recessive spastic paraplegia type 70
MARS1	Orphanet:440427	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

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
MARS1	HGNC:6898	ENSG00000166986	P56192	Methionine–tRNA ligase, cytoplasmic	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MARS1	Methionine–tRNA ligase, cytoplasmic	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MARS1	Enzyme (other)	yes	6.1.1.10	WHEP-TRS_dom, aa-tRNA-synth_I_CS, GST_C

Expression context

Cohort genes with no expression data: 0.

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	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MARS1	301	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MARS1	5,727

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MARS1	P56192	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Cytosolic tRNA aminoacylation	1	439.2×	0.014	MARS1
tRNA Aminoacylation	1	285.5×	0.014	MARS1
Selenoamino acid metabolism	1	196.9×	0.014	MARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.014	MARS1
MITF-M-regulated melanocyte development	1	114.2×	0.018	MARS1
Metabolism of amino acids and derivatives	1	67.6×	0.023	MARS1
Translation	1	62.1×	0.023	MARS1
Developmental Biology	1	14.5×	0.086	MARS1
Metabolism of proteins	1	12.4×	0.086	MARS1
Metabolism	1	11.6×	0.086	MARS1

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
methionyl-tRNA aminoacylation	1	8426.0×	7e-04	MARS1
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	1532.0×	0.002	MARS1
rRNA transcription	1	991.3×	0.002	MARS1
tRNA aminoacylation for protein translation	1	842.6×	0.002	MARS1
cellular response to platelet-derived growth factor stimulus	1	648.1×	0.002	MARS1
cellular response to epidermal growth factor stimulus	1	318.0×	0.003	MARS1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Molgramostim	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Regramostim, Rituximab, Sargramostim.

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MARS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MARS1	26	Binding:26

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MARS1	6.1.1.10	methionine-tRNA ligase

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	MARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
MARS1	26	—

Clinical trials & evidence

Clinical trials

Clinical trials: 21.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	12
PHASE2	5
PHASE1	2
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06989333	PHASE2	NOT_YET_RECRUITING	Local Spraying of GM-CSF Via Bronchoscopy in the Treatment of Autoimmune Pulmonary Alveolar Proteinosis
NCT00030056	PHASE2	TERMINATED	GM-CSF in Patients With Pulmonary Alveolar Proteinosis
NCT00552461	PHASE2	COMPLETED	Prospective Trial of Rituximab for Primary Pulmonary Alveolar Proteinosis
NCT01983657	PHASE2	UNKNOWN	Study of Subcutaneous Injection of Low-dose rhGM-CSF +/- WLL in PAP.
NCT03316651	PHASE2	UNKNOWN	Sequential Therapy With WLL/Inhaling GM-CSF for Autoimmune Pulmonary Alveolar Proteinosis
NCT03887169	PHASE1/PHASE2	COMPLETED	Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.
NCT01842386	PHASE1	COMPLETED	Rituximab for Anti-cytokine Autoantibody-Associated Diseases
NCT02468908	PHASE1	COMPLETED	Inhaled Molgramostim (rhGM-CSF) in Healthy Adult Subjects
NCT04326036	EARLY_PHASE1	UNKNOWN	Use of cSVF Via IV Deployment for Residual Lung Damage After Symptomatic COVID-19 Infection
NCT00461188	Not specified	RECRUITING	Genetics of Endocrine Tumours - Familial Isolated Pituitary Adenoma - FIPA
NCT02461615	Not specified	RECRUITING	A National Registry For Pulmonary Alveolar Proteinosis
NCT02852928	Not specified	RECRUITING	European Management Platform for Childhood Interstitial Lung Diseases - chILD-EU Register and Biobank
NCT06767111	Not specified	ENROLLING_BY_INVITATION	Techcyte SureView Cervical Cytology System Clinical Validation Study
NCT02081092	Not specified	COMPLETED	Evaluation and Treatment Planning of Patients With PAP Using Thrive Ultra Short Echo Time MRI and CT
NCT03007134	Not specified	COMPLETED	Multicenter International Cross-Sectional Evaluation of Pulmonary Alveolar Proteinosis Trial
NCT03721445	Not specified	UNKNOWN	Could HRV be a Valuable Predictor for CPAP Adherence?
NCT04516577	Not specified	COMPLETED	Updated Severity and Prognosis Score of Pulmonary Alveolar Proteinosis
NCT04811274	Not specified	COMPLETED	Macrophages, GM-CSF and MARS Proteinosis
NCT05300360	Not specified	UNKNOWN	Prevalence of Adenosine Deaminase (ADA) Enzyme Deficiency Disease in Adult Patients With Pulmonary Alveolar Proteinosis
NCT05640687	Not specified	UNKNOWN	The Study of Mesenchymal Stem Cells Treat Autoimmune Pulmonary Alveolar Proteinosis in Vitro
NCT06930989	Not specified	COMPLETED	Primary Prevention Long-term Registry Study in OSA and Hypertension. Survival Analysis 2010-2022

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RITUXIMAB	4	2
CYANOCOBALAMIN	4	1
REGRAMOSTIM	3	2
METHIONINE	3	1
MOLGRAMOSTIM	3	1
CHEMBL1234268	0	1
CHEMBL4303681	0	1
VITAMIN B12	0	1
RACEMETHIONINE	-1	1