severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Summary

severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (MONDO:0014206) is a disease caused by MARS1 (GenCC Strong), with 6 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MARS1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 817
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		26	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
Mondo ID	MONDO:0014206
OMIM	615486
Orphanet	440427
UMLS	C4225400
MedGen	895551
GARD	0017746
Is cancer (heuristic)	no

Also known as: hereditary pulmonary alveolar proteinosis with hepatic involvement · ILLD · infantile liver failure syndrome 2 · interstitial lung and liver disease · PAP, Reunion island type · pulmonary alveolar proteinosis, Reunion island type

Data availability: 817 ClinVar variants · 3 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 › severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Related subtypes (7): surfactant metabolism dysfunction, pulmonary, 1, surfactant metabolism dysfunction, pulmonary, 4, interstitial lung disease due to ABCA3 deficiency, surfactant metabolism dysfunction, pulmonary, 5, 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

600 retrieved; paginated sample, class counts are floors:

342 uncertain significance, 223 likely benign, 14 conflicting classifications of pathogenicity, 11 benign/likely benign, 7 benign, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
189364	NM_004990.3(MARS):c.[1700C>T;1177G>A]		Pathogenic	no assertion criteria provided
189365	NM_004990.4(MARS1):c.1814A>T (p.Asp605Val)	MARS1	Pathogenic	no assertion criteria provided
1172762	NM_004990.4(MARS1):c.1547A>G (p.Tyr516Cys)	MARS1	Likely pathogenic	criteria provided, single submitter
1032278	NM_004990.4(MARS1):c.1294-19C>G	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1056553	NM_004990.4(MARS1):c.1792C>T (p.Arg598Cys)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163539	NM_004990.4(MARS1):c.212del (p.Leu71fs)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172763	NM_004990.4(MARS1):c.1793G>A (p.Arg598His)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681687	NM_004990.4(MARS1):c.323A>G (p.Lys108Arg)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681720	NM_004990.4(MARS1):c.1127G>A (p.Arg376Gln)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681736	NM_004990.4(MARS1):c.1422G>C (p.Trp474Cys)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681737	NM_004990.4(MARS1):c.1445C>T (p.Thr482Ile)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681773	NM_004990.4(MARS1):c.2114dup (p.Leu705fs)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1799748	NM_004990.4(MARS1):c.2392-5dup	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1800266	NM_004990.4(MARS1):c.491-5C>G	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242615	NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
384378	NM_004990.4(MARS1):c.1540-3C>T	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389593	NM_004990.4(MARS1):c.2391A>C (p.Thr797=)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1186581	NM_004990.4(MARS1):c.31G>A (p.Gly11Ser)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
120186	NM_004990.4(MARS1):c.13G>A (p.Val5Met)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681667	NM_004990.4(MARS1):c.2T>A (p.Met1Lys)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1681668	NM_004990.4(MARS1):c.67C>G (p.Arg23Gly)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1681672	NM_004990.4(MARS1):c.109+7GTGCTG[3]	ARHGAP9	Uncertain significance	criteria provided, single submitter
1800437	NM_004990.4(MARS1):c.79G>A (p.Glu27Lys)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1939722	NM_004990.4(MARS1):c.5G>C (p.Arg2Thr)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1944205	NM_004990.4(MARS1):c.86T>C (p.Leu29Pro)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1965121	NM_004990.4(MARS1):c.73A>G (p.Arg25Gly)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1980062	NM_004990.4(MARS1):c.109G>A (p.Asp37Asn)	ARHGAP9	Uncertain significance	criteria provided, single submitter
2059873	NM_004990.4(MARS1):c.71G>C (p.Gly24Ala)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2190158	NM_004990.4(MARS1):c.89T>G (p.Ile30Ser)	ARHGAP9	Uncertain significance	criteria provided, single submitter
2925127	NM_004990.4(MARS1):c.31G>C (p.Gly11Arg)	ARHGAP9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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
MARS1	Strong	Autosomal recessive	severe early-onset pulmonary alveolar proteinosis due to MARS deficiency	12

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
FARSB	Orphanet:178506	Interstitial lung disease-brain calcification syndrome
SDR9C7	Orphanet:313	Lamellar ichthyosis
SDR9C7	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MARS1	HGNC:6898	ENSG00000166986	P56192	Methionine–tRNA ligase, cytoplasmic	gencc,clinvar
ARHGAP9	HGNC:14130	ENSG00000123329	Q9BRR9	Rho GTPase-activating protein 9	clinvar
FARSB	HGNC:17800	ENSG00000116120	Q9NSD9	Phenylalanine–tRNA ligase beta subunit	clinvar
SLC30A7	HGNC:19306	ENSG00000162695	Q8NEW0	Zinc transporter 7	clinvar
DCTN2	HGNC:2712	ENSG00000175203	Q13561	Dynactin subunit 2	clinvar
SDR9C7	HGNC:29958	ENSG00000170426	Q8NEX9	Short-chain dehydrogenase/reductase family 9C member 7	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.
ARHGAP9	Rho GTPase-activating protein 9	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
SLC30A7	Zinc transporter 7	Zinc ion transporter mediating zinc entry from the cytosol into the lumen of organelles along the secretory pathway.
DCTN2	Dynactin subunit 2	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
SDR9C7	Short-chain dehydrogenase/reductase family 9C member 7	Plays a crucial role in the formation of the epidermal permeability barrier.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 3 · 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
Enzyme (other)	2	4.0×	0.249
Scaffold/PPI	1	2.9×	0.451
Other/Unknown	3	0.9×	0.758

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
ARHGAP9	Scaffold/PPI	no		RhoGAP_dom, WW_dom, SH3_domain
FARSB	Enzyme (other)	yes	6.1.1.20	Phe-tRNA-synth_IIc_bsu_arc_euk, B3/B4_tRNA-bd, tRNA_synthase_B5-dom
SLC30A7	Other/Unknown	no		Cation_efflux, Cation_efflux_TMD_sf, Msc2-like
DCTN2	Other/Unknown	no		Dynamitin
SDR9C7	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
blood	1
granulocyte	1
spleen	1
cardiac muscle of right atrium	1
gingival epithelium	1
left ventricle myocardium	1
buccal mucosa cell	1
oviduct epithelium	1
pancreatic ductal cell	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
skin of abdomen	1
skin of leg	1
zone of skin	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
ARHGAP9	235	broad	marker	granulocyte, blood, spleen
FARSB	264	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, gingival epithelium
SLC30A7	249	ubiquitous	marker	oviduct epithelium, pancreatic ductal cell, buccal mucosa cell
DCTN2	295	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
SDR9C7	113	tissue_specific	yes	skin of leg, skin of abdomen, zone of skin

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MARS1	5,727
FARSB	3,392
DCTN2	2,922
ARHGAP9	1,748
SLC30A7	1,374
SDR9C7	785

Intra-cohort edges

A	B	Sources
FARSB	MARS1	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MARS1	P56192	7
SLC30A7	Q8NEW0	7
ARHGAP9	Q9BRR9	3
FARSB	Q9NSD9	3
DCTN2	Q13561	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SDR9C7	Q8NEX9	93.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 6 evidence-associated genes (5 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 5 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	2	175.7×	0.001	MARS1, FARSB
tRNA Aminoacylation	2	114.2×	0.002	MARS1, FARSB
Translation	2	24.8×	0.022	MARS1, FARSB
The canonical retinoid cycle in rods (twilight vision)	1	103.8×	0.062	SDR9C7
COPI-independent Golgi-to-ER retrograde traffic	1	41.5×	0.068	DCTN2
Selenoamino acid metabolism	1	39.4×	0.068	MARS1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	38.7×	0.068	DCTN2
Transcriptional and post-translational regulation of MITF-M expression and activity	1	35.7×	0.068	MARS1
Loss of Nlp from mitotic centrosomes	1	31.7×	0.068	DCTN2
Loss of proteins required for interphase microtubule organization from the centrosome	1	31.7×	0.068	DCTN2
AURKA Activation by TPX2	1	30.4×	0.068	DCTN2
Recruitment of mitotic centrosome proteins and complexes	1	27.2×	0.068	DCTN2
Regulation of PLK1 Activity at G2/M Transition	1	25.4×	0.068	DCTN2
Recruitment of NuMA to mitotic centrosomes	1	23.3×	0.068	DCTN2
MITF-M-regulated melanocyte development	1	22.8×	0.068	MARS1
Anchoring of the basal body to the plasma membrane	1	22.6×	0.068	DCTN2
COPI-mediated anterograde transport	1	22.0×	0.068	DCTN2
MHC class II antigen presentation	1	17.8×	0.076	DCTN2
Metabolism of proteins	2	5.0×	0.076	MARS1, FARSB
RHOA GTPase cycle	1	14.9×	0.083	ARHGAP9
CDC42 GTPase cycle	1	14.5×	0.083	ARHGAP9
Metabolism of amino acids and derivatives	1	13.5×	0.085	MARS1
RAC1 GTPase cycle	1	12.2×	0.090	ARHGAP9
Neutrophil degranulation	1	4.6×	0.215	ARHGAP9
Developmental Biology	1	2.9×	0.313	MARS1
Metabolism	1	2.3×	0.362	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 6 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	1404.3×	0.009	MARS1
zinc ion import into Golgi lumen	1	936.2×	0.009	SLC30A7
phenylalanyl-tRNA aminoacylation	1	702.2×	0.009	FARSB
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	255.3×	0.018	MARS1
protein heterotetramerization	1	175.5×	0.018	FARSB
rRNA transcription	1	165.2×	0.018	MARS1
tRNA aminoacylation for protein translation	1	140.4×	0.018	MARS1
melanosome transport	1	127.7×	0.018	DCTN2
protein localization to centrosome	1	112.3×	0.018	DCTN2
cellular response to platelet-derived growth factor stimulus	1	108.0×	0.018	MARS1
retinol metabolic process	1	82.6×	0.020	SDR9C7
intracellular zinc ion homeostasis	1	80.2×	0.020	SLC30A7
mitotic metaphase chromosome alignment	1	63.8×	0.023	DCTN2
steroid metabolic process	1	56.2×	0.024	SDR9C7
cellular response to epidermal growth factor stimulus	1	53.0×	0.024	MARS1
mitotic spindle organization	1	45.3×	0.026	DCTN2
small GTPase-mediated signal transduction	1	30.5×	0.036	ARHGAP9
regulation of small GTPase mediated signal transduction	1	24.0×	0.043	ARHGAP9
translation	1	17.1×	0.057	FARSB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 3 of 6 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
FARSB	3	2
MARS1	0	0
ARHGAP9	0	0
SLC30A7	0	0
DCTN2	0	0
SDR9C7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	FARSB
TANDUTINIB	2	FARSB
PHA-793887	1	FARSB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
MARS1	26	Binding:26
FARSB	8	Binding:8
SLC30A7	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MARS1	6.1.1.10	methionine-tRNA ligase
FARSB	6.1.1.20	phenylalanine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	FARSB
TANDUTINIB	2	FARSB
PHA-793887	1	FARSB

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	1	FARSB
C	Druggable family + PDB, no drug	1	MARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	ARHGAP9, SLC30A7, DCTN2, SDR9C7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MARS1	26	—
ARHGAP9	0	—
SLC30A7	1	—
DCTN2	0	—
SDR9C7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05514470	Not specified	WITHDRAWN	Impact of Mutations in Aminoacyl tRNA Synthetases on Protein Translation and Cellular Stress