SFTPC

Summary

SFTPC (surfactant protein C, HGNC:10802) is a protein-coding gene on chromosome 8p21.3, encoding Surfactant protein C (P11686). Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.

This gene encodes the pulmonary-associated surfactant protein C (SPC), an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 2, also called pulmonary alveolar proteinosis due to surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and adults. Alternatively spliced transcript variants encoding different protein isoforms have been identified.

Source: NCBI Gene 6440 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SFTPC-related interstitial lung disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 205 total — 15 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 59
• MANE Select transcript: NM_001317778

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10802
Approved symbol	SFTPC
Name	surfactant protein C
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	SP-C, PSP-C, SMDP2, BRICD6
Ensembl gene	ENSG00000168484
Ensembl biotype	protein_coding
OMIM	178620
Entrez	6440

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000318561, ENST00000437090, ENST00000518615, ENST00000520605, ENST00000521315, ENST00000522109, ENST00000522630, ENST00000522880, ENST00000523296, ENST00000524255, ENST00000524318, ENST00000524350, ENST00000679463, ENST00000905723, ENST00000905727, ENST00000950317, ENST00000950318, ENST00000950319, ENST00000950320, ENST00000950321

RefSeq mRNA: 14 — MANE Select: NM_001317778 NM_001172357, NM_001172410, NM_001317778, NM_001317779, NM_001317780, NM_001385653, NM_001385654, NM_001385655, NM_001385656, NM_001385657, NM_001385658, NM_001385659, NM_001385660, NM_003018

CCDS: CCDS43722, CCDS55209, CCDS83259

Canonical transcript exons

ENST00000679463 — 6 exons

Exon	Start	End
ENSE00001159094	22163436	22163546
ENSE00001159100	22163080	22163202
ENSE00002127421	22161798	22161870
ENSE00003663678	22162574	22162732
ENSE00003675629	22164266	22164479
ENSE00003913133	22163901	22164059

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 99.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 16.9132 / max 12249.9552, expressed in 39 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87714	16.4894	14
205099	0.1175	6
87721	0.0749	7
87719	0.0393	6
87716	0.0379	5
87713	0.0366	20
87720	0.0294	4
205101	0.0256	6
87717	0.0159	3
87718	0.0117	3

Top tissues by expression

264 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	99.98	gold quality
right lung	UBERON:0002167	99.91	gold quality
adult organism	UBERON:0007023	99.89	gold quality
upper lobe of lung	UBERON:0008948	99.73	gold quality
upper lobe of left lung	UBERON:0008952	99.71	gold quality
visceral pleura	UBERON:0002401	98.66	gold quality
lung	UBERON:0002048	98.41	gold quality
tendon of biceps brachii	UBERON:0008188	95.00	silver quality
buccal mucosa cell	CL:0002336	89.65	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	88.70	gold quality
parotid gland	UBERON:0001831	87.92	silver quality
apex of heart	UBERON:0002098	87.53	gold quality
spinal cord	UBERON:0002240	86.98	gold quality
medial globus pallidus	UBERON:0002477	86.49	gold quality
vena cava	UBERON:0004087	86.27	gold quality
putamen	UBERON:0001874	85.48	gold quality
heart right ventricle	UBERON:0002080	85.04	silver quality
globus pallidus	UBERON:0001875	84.93	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	83.65	silver quality
right frontal lobe	UBERON:0002810	83.59	gold quality
inferior olivary complex	UBERON:0002127	83.56	gold quality
caudate nucleus	UBERON:0001873	83.24	gold quality
nucleus accumbens	UBERON:0001882	83.13	gold quality
amygdala	UBERON:0001876	83.00	gold quality
tongue squamous epithelium	UBERON:0006919	82.68	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.00	silver quality
prefrontal cortex	UBERON:0000451	81.66	gold quality
substantia nigra	UBERON:0002038	81.61	gold quality
type B pancreatic cell	CL:0000169	81.21	gold quality
midbrain	UBERON:0001891	81.07	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	163631.52
E-GEOD-130148	yes	147535.04
E-CURD-126	yes	142486.86
E-MTAB-6308	yes	134248.65
E-HCAD-1	yes	119650.34
E-MTAB-6653	yes	114081.93
E-GEOD-86618	yes	20710.15
E-ANND-2	yes	14275.04
E-MTAB-8221	yes	11025.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETV5, FOXM1, FOXP1, FOXP2, GATA4, GATA6, HESX1, NFIC, NKX2-1, PLAGL2, PRDM2, TTF1, ZNF91

miRNA regulators (miRDB)

6 targeting SFTPC, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-3667-5P	97.16	64.87	591

Literature-anchored findings (GeneRIF, showing 40)

• review of lipid-protein interactions of hydrophobic proteins SP-B and SP-C in lung surfactant assembly and dynamics (PMID:11699574)
• review of synthesis and post-translational processing of surfactant protein C (PMID:11699575)
• mutations causally related to familial interstitial lung disease (PMID:11893657)
• Biosynthesis of surfactant protein C (SP-C). Sorting of SP-C proprotein involves homomeric association via a signal anchor domain (PMID:11907042)
• associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred (PMID:11991887)
• role of cathepsin H in processing in pneumocytes (PMID:12034564)
• surfactant protein C processing requires a type II transmembrane topology directed by juxtamembrane positively charged residues (PMID:12933801)
• surfactant protein C has a role in interstitial lung disease and lung development (PMID:14525980)
• Current state of knowledge concerning the lung diseases associated with mutations in the SP-B and SP-C genes, and the potential roles of abnormal SP-B and SP-C expression and genetic variation in these genes in other lung diseases. Review. (PMID:14977415)
• An incompletely processed form of SP-C precursor found in association with childhood SP-B deficiency associates with surfactant phospholipids and is secreted into the airspaces with the large aggregate form of surfactant, but it lacks surface activity. (PMID:15049696)
• Observations suggest that individuals with this particular mutation in surfactant protein C gene might be at increased risk of interstitial lung disease of variety of types. (PMID:15133475)
• NMR solution structure and analysis of potential C-terminal dimerization site of a recombinant mutant of surfactant-associated protein C. (PMID:15153097)
• Missense mutation of the surfactant protein C gene is associated with interstitial lung disease in newborn. (PMID:15293602)
• most premature infants requiring continued respiratory support after 7 d of age experience transient episodes of dysfunctional surfactant that are associated with a deficiency of SP-B and SP-C. (PMID:15496605)
• proSP-C BRICHOS mutations induce a dynamic toxic gain-of-function, causing apoptotic cell death both by early ER accumulation leading to an exaggerated unfolded protein response and by enhanced deposition of cellular aggregates associated with proteasome (PMID:15778495)
• Immuno-analysis of the hydrophobic surfactant proteins and their precursor forms in bronchoalveolar lavage is minimally invasive and can give valuable clues for the involvement of processing abnormalities in pediatric pulmonary disorders. (PMID:16042774)
• Infection of cells expressing mutant SP-C with respiratory syncytial virus resulted in significantly enhanced cytotoxicity associated with accumulation of the mutant proprotein, pronounced activation of the unfolded protein response, and cell death. (PMID:16449190)
• Erm is involved in SP-C regulation, which results from an interaction with TTF-1 (PMID:16613858)
• Via promoter mutation analysis, adjacent TTF-1 binding sites within the proximal promoter region of SP-C were found to be essential for TTF-1/TAP26-enhanced SP-C promoter activity. (PMID:16630564)
• Recombinant SP-C forms improved movement of phospholipid molecules into the interface (during adsorption), or out from the interfacial film (during compression) (PMID:16631109)
• Brichos domain-containing C-terminal part of pro-surfactant protein C binds to an unfolded poly-val transmembrane segment (PMID:16709565)
• The influence of palmitoylation was studied for full length SP-Cs as well as truncated variants with the N-terminal residues 1-17 and 1-13, respectively. (PMID:17051367)
• an inverse SFTPC haplotype distribution was found between children with asthma and respiratory syncytial virus infection (PMID:17121584)
• These results suggest common cellular responses, including initiation of cell-death signaling pathways, to these lung disease-associated SP-C BRICHOS domain proteins. (PMID:17586700)
• finding of heterozygosity for ABCA3 mutations in severely affected infants with SFTPC I73T, and independent inheritance from disease-free parents supports that ABCA3 acts as a modifier gene for the phenotype associated with an SFTPC mutation. (PMID:17597647)
• Data show that the exposed hydrophobic surfaces and the structural disordering that result from interactions with phospholipid membranes suggest a mechanism whereby C-terminal part of proSP-C binds to misfolded SP-C in the endoplasmic reticulum membrane. (PMID:18199284)
• Data show that direct interaction between Foxp2 and Nkx2.1 inhibits Nkx2.1 DNA-binding and transcriptional activity and suggest a mechanism for down-regulation of SP-C during transition of AT2 cells to an AT1 cell phenotype. (PMID:18239190)
• Determined population-based frequencies of SP-C mutations in newborn respiratory distress syndrome. (PMID:18317237)
• Required for successful fetal-neonatal pulmonary transition (PMID:18383112)
• After demonstrating unfolded protein response (UPR) activation in cultured A549 cells expressing mutant SFTPC, we identified prominent expression of UPR markers in AECs in the lungs of patients with SFTPC mutation-associated fibrosis. (PMID:18390830)
• ERdj4 and ERdj5 promote turnover of misfolded SP-C and this activity is dependent on their ability to stimulate BiP ATPase activity. (PMID:18400946)
• Concentration or molecular form of SP-B and SP-C is not altered in bronchoalveolar lavage fluid of children with different acute and chronic inflammatory lung diseases. (PMID:18405368)
• Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand, protein C. (PMID:18612544)
• Mutations in the C-terminal domain of SP-C may lead to interstitial lung disease by a lo of SP-C chaperone function. (PMID:18643778)
• confirms the value of genetic screening for surfactant protein genes mutations.These cases provide new insight into the variability of the disease phenotype. (PMID:19148933)
• mutations in the SP-C gene SFTPC are more commonly associated with interstitial lung disease in older infants, children, and adults (PMID:19220077)
• Carboxy-terminal domain of lung surfactant protein C precursor functions as a chaperone that acts preferentially against unfolded transmembrane segments found during amyloid fibril formation and prevents amyloid beta1-40 aggregation and fibril formation. (PMID:19281242)
• the Nedd4/proSP-C tandem is part of a larger protein complex containing a ubiquitinated component that further directs its transport (PMID:19366705)
• PSP-C C-terminal domain binds to all amino acid residues that promote membrane insertion, provided that they are in a nonhelical conformation; prevents PSP-C amyloid fibril formation (PMID:19376131)
• Studied surfactant protein C gene (SFTPC) mutations in a large cohort of infants and children with diffuse lung disease. Ten unrelated patients were shown to carry the common SFTPC mutation, p.Ile73Thr (I73T). (PMID:19443464)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sftpc	ENSMUSG00000022097
rattus_norvegicus	Sftpc	ENSRNOG00000011177

Protein

Protein identifiers

Surfactant protein C — P11686 (reviewed: P11686)

Alternative names: Pulmonary surfactant-associated protein C, Pulmonary surfactant-associated proteolipid SPL(Val), SP5

All UniProt accessions (7): P11686, A0A0S2Z4Q0, C9JYF6, E5RG20, E5RHW5, E5RI64, E5RI92

UniProt curated annotations — full annotation on UniProt →

Function. Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.

Subcellular location. Secreted. Extracellular space. Surface film.

Disease relevance. Pulmonary surfactant metabolism dysfunction 2 (SMDP2) [MIM:610913] A rare disease associated with progressive respiratory insufficiency and lung disease with a variable clinical course, due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Pulmonary surfactant consists of 90% lipid and 10% protein. There are 4 surfactant-associated proteins: 2 collagenous, carbohydrate-binding glycoproteins (SP-A and SP-D) and 2 small hydrophobic proteins (SP-B and SP-C).

Isoforms (2)

UniProt ID	Names	Canonical?
P11686-1	1	yes
P11686-2	2, C1

RefSeq proteins (14): NP_001165828, NP_001165881, NP_001304707, NP_001304708, NP_001304709, NP_001372582, NP_001372583, NP_001372584, NP_001372585, NP_001372586, NP_001372587, NP_001372588, NP_001372589, NP_003009 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001729	SP-C	Family
IPR007084	BRICHOS_dom	Domain
IPR015091	Surfactant_protein_propep	Domain
IPR018051	SP-C_palmitoylation_site	PTM

Pfam: PF04089, PF08999

UniProt features (34 total): strand 9, sequence variant 7, sequence conflict 3, turn 3, helix 3, propeptide 2, lipid moiety-binding region 2, disulfide bond 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2YAD	X-RAY DIFFRACTION	2.2
8OVI	SOLUTION NMR
8OX2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11686-F1	70.71	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 28, 29

Disulfide bonds (2): 120–148, 121–189

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5683826	Surfactant metabolism
R-HSA-5688354	Defective pro-SFTPC causes SMDP2 and RDS
R-HSA-5688849	Defective CSF2RB causes SMDP5
R-HSA-5688890	Defective CSF2RA causes SMDP4

MSigDB gene sets: 227 (showing top): RNGTGGGC_UNKNOWN, AP1_01, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOCC_SECRETORY_GRANULE, GCANCTGNY_MYOD_Q6, MODULE_45, MODULE_16, MODULE_118, chr8p21, BLALOCK_ALZHEIMERS_DISEASE_UP, GOCC_COATED_VESICLE, BACH2_01, NAKAMURA_LUNG_CANCER_DIFFERENTIATION_MARKERS, TGANTCA_AP1_C

GO Biological Process (1): respiratory gaseous exchange by respiratory system (GO:0007585)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), lamellar body (GO:0042599), clathrin-coated endocytic vesicle (GO:0045334), alveolar lamellar body (GO:0097208), multivesicular body lumen (GO:0097486), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Diseases associated with surfactant metabolism	3
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
multicellular organismal process	1
protein binding	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
secretory granule	1
clathrin-coated vesicle	1
endocytic vesicle	1
lamellar body	1
multivesicular body	1
late endosome lumen	1

Protein interactions and networks

STRING

1238 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SFTPC	SFTPA2	P07714	991
SFTPC	SFTPB	P07988	991
SFTPC	X6REF7	X6REF7	971
SFTPC	SFTPD	P35247	944
SFTPC	PIGR	P01833	904
SFTPC	ABCA3	Q99758	895
SFTPC	SCGB1A1	P11684	856
SFTPC	VTN	P01141	813
SFTPC	ITGB4	P16144	811
SFTPC	AQP5	P55064	799
SFTPC	NKX2-1	P43699	771
SFTPC	FOXJ1	Q92949	770
SFTPC	HOPX	Q9BPY8	669
SFTPC	MUC5B	Q9HC84	667
SFTPC	P3H3	Q8IVL6	666

IntAct

130 interactions, top by confidence:

A	B	Type	Score
TMEM79	SFTPC	psi-mi:“MI:0915”(physical association)	0.900
SFTPC	TMEM79	psi-mi:“MI:0915”(physical association)	0.900
SFTPC	SFTPC	psi-mi:“MI:0915”(physical association)	0.830
SFTPC	CXCL9	psi-mi:“MI:0915”(physical association)	0.780
CXCL9	SFTPC	psi-mi:“MI:0915”(physical association)	0.780
SFTPC	SEC22A	psi-mi:“MI:0915”(physical association)	0.720
SEC22A	SFTPC	psi-mi:“MI:0915”(physical association)	0.720
SFTPC	PVR	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (245): SFTPC (Two-hybrid), SFTPC (Two-hybrid), SEC61G (Two-hybrid), SEC22A (Two-hybrid), TMEM79 (Two-hybrid), SYNE4 (Two-hybrid), CREB3 (Two-hybrid), SFTPC (Two-hybrid), SMIM3 (Two-hybrid), SYNE4 (Two-hybrid), TMEM79 (Two-hybrid), NPTXR (Affinity Capture-MS), CBX8 (Affinity Capture-MS), CBX6 (Affinity Capture-MS), SCARF2 (Affinity Capture-MS)

ESM2 similar proteins: A2VDN0, A5A6H8, B5DFM7, E1B9E5, O18638, O42204, O43736, O70367, O75829, O77770, O89051, P11685, P11686, P15783, P21841, P35245, P55152, P58239, Q06AV4, Q14956, Q29TV8, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5R876, Q5XIE8, Q60HC1, Q61500, Q6AYE5, Q6GPK2, Q6P7C7, Q71SY6, Q86UD1, Q86XP6, Q8HYA9, Q8QZR4, Q90372, Q91VK4

Diamond homologs: P11685, P11686, P15783, P15785, P21841, P22398, P35245, P55152

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLAGL2	“up-regulates quantity by expression”	SFTPC	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	21.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

205 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	12
Uncertain significance	80
Likely benign	32
Benign	28

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
13207	NM_001317778.2(SFTPC):c.435+1G>A	Pathogenic
13210	NM_001317778.2(SFTPC):c.545T>A (p.Leu182Gln)	Pathogenic
13211	NM_001317778.2(SFTPC):c.435+1G>T	Pathogenic
13212	NM_001317778.2(SFTPC):c.347C>A (p.Ala116Asp)	Pathogenic
13213	NM_001317778.2(SFTPC):c.196G>A (p.Glu66Lys)	Pathogenic
13214	NM_001317778.2(SFTPC):c.563T>C (p.Leu188Pro)	Pathogenic
1492510	NM_001317778.2(SFTPC):c.435+2T>C	Pathogenic
1738082	NM_001317778.2(SFTPC):c.413_430delinsAGGTGATC (p.Thr138fs)	Pathogenic
1744578	NM_001317778.2(SFTPC):c.480dup (p.Arg161fs)	Pathogenic
2735138	NM_001317778.2(SFTPC):c.313G>T (p.Asp105Tyr)	Pathogenic
2735139	NM_001317778.2(SFTPC):c.325-1G>A	Pathogenic
2861268	NM_001317778.2(SFTPC):c.400del (p.Glu135fs)	Pathogenic
3350398	NM_001317778.2(SFTPC):c.325-2A>C	Pathogenic
4726413	NM_001317778.2(SFTPC):c.325-1G>C	Pathogenic
4820074	NM_001317778.2(SFTPC):c.362G>T (p.Cys121Phe)	Pathogenic
1065347	NM_001317778.2(SFTPC):c.444del (p.Ala149fs)	Likely pathogenic
1333368	NM_001317778.2(SFTPC):c.314A>T (p.Asp105Val)	Likely pathogenic
1700691	NM_001317778.2(SFTPC):c.192C>G (p.His64Gln)	Likely pathogenic
1730508	NM_001317778.2(SFTPC):c.334G>C (p.Ala112Pro)	Likely pathogenic
1730814	NM_001317778.2(SFTPC):c.337T>C (p.Tyr113His)	Likely pathogenic
1739999	NM_001317778.2(SFTPC):c.435G>A (p.Gln145=)	Likely pathogenic
1744270	NM_001317778.2(SFTPC):c.476_477del (p.Glu159fs)	Likely pathogenic
3235892	NM_001317778.2(SFTPC):c.481C>T (p.Arg161Ter)	Likely pathogenic
3720805	NM_001317778.2(SFTPC):c.314A>G (p.Asp105Gly)	Likely pathogenic
521813	NM_001317778.2(SFTPC):c.397A>C (p.Ser133Arg)	Likely pathogenic
598978	NM_001317778.2(SFTPC):c.163C>T (p.Leu55Phe)	Likely pathogenic
802394	NM_001317778.2(SFTPC):c.316T>C (p.Tyr106His)	Likely pathogenic

SpliceAI

784 predictions. Top by Δscore:

Variant	Effect	Δscore
8:22162558:T:TA	acceptor_gain	1.0000
8:22162566:C:CA	acceptor_gain	1.0000
8:22162729:GATG:G	donor_gain	1.0000
8:22163076:CCAG:C	acceptor_loss	1.0000
8:22163078:A:AC	acceptor_loss	1.0000
8:22163078:A:AG	acceptor_gain	1.0000
8:22163078:AG:A	acceptor_gain	1.0000
8:22163079:G:GT	acceptor_gain	1.0000
8:22163079:GG:G	acceptor_gain	1.0000
8:22163199:GCAG:G	donor_gain	1.0000
8:22163200:CAG:C	donor_loss	1.0000
8:22163202:GG:G	donor_loss	1.0000
8:22163203:G:GG	donor_gain	1.0000
8:22163434:A:AG	acceptor_gain	1.0000
8:22163435:G:GG	acceptor_gain	1.0000
8:22161867:GCCG:G	donor_gain	0.9900
8:22161868:CCGG:C	donor_loss	0.9900
8:22161870:GGTG:G	donor_loss	0.9900
8:22161871:G:A	donor_loss	0.9900
8:22161871:G:GG	donor_gain	0.9900
8:22162554:T:A	acceptor_gain	0.9900
8:22162564:A:AG	acceptor_gain	0.9900
8:22162564:ACC:A	acceptor_gain	0.9900
8:22162564:ACCGT:A	acceptor_gain	0.9900
8:22162565:C:G	acceptor_gain	0.9900
8:22162568:T:TA	acceptor_gain	0.9900
8:22162569:GTCA:G	acceptor_loss	0.9900
8:22162572:A:AG	acceptor_gain	0.9900
8:22162572:AG:A	acceptor_gain	0.9900
8:22162573:G:GG	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000316822 (8:22163102 C>T), RS1000587425 (8:22164423 C>T), RS1000607677 (8:22162238 G>A,C), RS1000642010 (8:22162097 C>T), RS1000657233 (8:22163286 C>A,T), RS1000909861 (8:22157383 A>C), RS1001062901 (8:22164169 G>T), RS1001095166 (8:22159169 T>C), RS1001448911 (8:22161650 G>A,T), RS1001643674 (8:22158410 A>C), RS1001777224 (8:22161809 A>G,T), RS1001942818 (8:22158074 G>A), RS1001980426 (8:22159568 AAGG>A), RS1002092052 (8:22164783 G>A), RS1002351984 (8:22157806 A>G)

Disease associations

OMIM: gene MIM:178620 | disease phenotypes: MIM:610913, MIM:265120, MIM:178500

GenCC curated gene-disease

Disease	Classification	Inheritance
surfactant metabolism dysfunction, pulmonary, 2	Definitive	Autosomal dominant
chronic respiratory distress with surfactant metabolism deficiency	Supportive	Autosomal dominant
SFTPC-related interstitial lung disease	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
SFTPC-related interstitial lung disease	Definitive	AD

Mondo (7): surfactant metabolism dysfunction, pulmonary, 2 (MONDO:0024465), pulmonary fibrosis (MONDO:0002771), hereditary pulmonary alveolar proteinosis (MONDO:0012580), interstitial lung disease 2 (MONDO:0800497), surfactant metabolism dysfunction, pulmonary, 1 (MONDO:0009929), chronic respiratory distress with surfactant metabolism deficiency (MONDO:0016323), SFTPC-related interstitial lung disease (MONDO:0018603)

Orphanet (4): Hereditary pulmonary alveolar proteinosis (Orphanet:264675), Idiopathic pulmonary fibrosis (Orphanet:2032), Acute interstitial pneumonia (Orphanet:79126), Neonatal acute respiratory distress syndrome (Orphanet:217563)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000765	Abnormal thorax morphology
HP:0000961	Cyanosis
HP:0001063	Acrocyanosis
HP:0001217	Clubbing
HP:0001263	Global developmental delay
HP:0001394	Cirrhosis
HP:0001508	Failure to thrive
HP:0001622	Premature birth
HP:0001649	Tachycardia
HP:0001662	Bradycardia
HP:0001695	Cardiac arrest
HP:0002020	Gastroesophageal reflux
HP:0002090	Pneumonia
HP:0002092	Pulmonary arterial hypertension
HP:0002093	Respiratory insufficiency
HP:0002094	Dyspnea
HP:0002098	Respiratory distress
HP:0002108	Spontaneous pneumothorax
HP:0002110	Bronchiectasis
HP:0002206	Pulmonary fibrosis
HP:0002615	Hypotension
HP:0002789	Tachypnea
HP:0002875	Exertional dyspnea
HP:0002878	Respiratory failure
HP:0003546	Exercise intolerance
HP:0005942	Desquamative interstitial pneumonitis
HP:0006515	Interstitial pneumonitis
HP:0006517	Intraalveolar phospholipid accumulation
HP:0006519	Alveolar cell carcinoma

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001905_1	Hypertriglyceridemia	7.000000e-06
GCST005194_87	Coronary artery disease	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D011658	Pulmonary Fibrosis	C08.381.483.652; C23.550.355.644
C535832	Pulmonary alveolar proteinosis, congenital (supp.)
C566882	Surfactant Metabolism Dysfunction, Pulmonary, 1 (supp.)
C567048	Surfactant Metabolism Dysfunction, Pulmonary, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Dexamethasone	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
terbufos	increases methylation	1
4-phenylbutyric acid	increases cleavage, increases expression, increases phosphorylation, decreases reaction	1
Chir 99021	affects cotreatment, increases expression	1
ormosil	affects binding, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Vehicle Emissions	increases abundance, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Fonofos	increases methylation	1
Colforsin	increases expression	1
Hydrocortisone	increases expression	1
Methylmercury Compounds	decreases expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Polyethylene Glycols	decreases expression, affects binding	1
Silicon Dioxide	decreases expression	1
Testosterone	increases expression	1
Tretinoin	affects cotreatment, increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression, affects cotreatment	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

206 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04619680	PHASE4	COMPLETED	The Study of the Use of Nintedanib in Slowing Lung Disease in Patients With Fibrotic or Non-Fibrotic Interstitial Lung Disease Related to COVID-19
NCT07570888	PHASE4	NOT_YET_RECRUITING	This is a Trial Designed to Evaluate the Combination of Nerandomilast With Mycophenolate Across a Wide Variety of Pulmonary Fibrosis Subtypes, With the Aim of Providing Clinicians With Assurance That This is an Appropriate Therapeutic Combination.
NCT00004563	PHASE3	COMPLETED	Scleroderma Lung Disease
NCT00052039	PHASE3	TERMINATED	A Randomized, Double-Blind, Three-Arm, Phase 3b Study Comparing the Safety and Efficacy of Interferon Gamma-1b With Azathioprine, and Azathioprine Alone in Patients With IPF Receiving Prednisone
NCT00075998	PHASE3	TERMINATED	The INSPIRE Trial: A Study of Interferon Gamma-1b for Idiopathic Pulmonary Fibrosis (IPF)
NCT00076635	PHASE3	TERMINATED	An Open-Label Study of the Safety of Interferon Gamma-1b in Patients With IPF
NCT00517933	PHASE3	COMPLETED	Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis
NCT00639496	PHASE3	COMPLETED	Study of the Effects of High-dose N-acetylcysteine (NAC) in Idiopathic Pulmonary Fibrosis (IPF)
NCT00650091	PHASE3	COMPLETED	Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in Patients With IPF
NCT00896155	PHASE3	UNKNOWN	Trial of Concurrent Versus Sequential Tamoxifen With Radiotherapy in Breast Cancer Patients
NCT01335464	PHASE3	COMPLETED	Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients
NCT01335477	PHASE3	COMPLETED	Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II
NCT01570764	PHASE3	COMPLETED	Cyclophosphamide Systemic Sclerosis Associated Interstitial Lung Disease
NCT03267108	PHASE3	TERMINATED	A Study to Assess Pulsed Inhaled Nitric Oxide in Subjects With Pulmonary Fibrosis at Risk for Pulmonary Hypertension
NCT04905693	PHASE3	ENROLLING_BY_INVITATION	Extension Study of Inhaled Treprostinil in Subjects With Fibrotic Lung Disease
NCT04979884	PHASE3	COMPLETED	Safety and Effectiveness of Cyclosporin in the Management of COVID19 ARDS Patients in Alexandria University Hospital
NCT05943535	PHASE3	RECRUITING	Study of the Efficacy and Safety of Inhaled Treprostinil in Subjects With Progressive Pulmonary Fibrosis (TETON-PPF)
NCT06025578	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of BMS-986278 in Participants With Progressive Pulmonary Fibrosis
NCT06238622	PHASE3	RECRUITING	A Follow-up Study to Test Long-term Treatment With Nerandomilast in People With Pulmonary Fibrosis Who Took Part in a Previous Study With Nerandomilast
NCT07201922	PHASE3	RECRUITING	A Study to Test Whether Nerandomilast Can Help Slow Down Changes in the Lung in People With a Family History of Pulmonary Fibrosis
NCT07441408	PHASE3	NOT_YET_RECRUITING	Long-term Extension Study to Evaluate Safety and Tolerability of Admilparant in Participants With Pulmonary Fibrosis
NCT07503587	PHASE3	NOT_YET_RECRUITING	Evaluating the Efficacy and Safety of of HSK44459 in People With Progressive Pulmonary Fibrosis
NCT00000596	PHASE2	COMPLETED	Diffuse Fibrotic Lung Disease
NCT00001596	PHASE2	COMPLETED	Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
NCT00052052	PHASE2	COMPLETED	An Open-Label Study of the Safety and Efficacy of Subcutaneous Recombinant Interferon-Gamma 1b (IFN-Gamma 1b) in Patients With Idiopathic Pulmonary Fibrosis (IPF)
NCT00063869	PHASE2	COMPLETED	Study Evaluating the Safety and Efficacy of Etanercept in Patients With Idiopathic Pulmonary Fibrosis
NCT00080223	PHASE2	COMPLETED	Safety Study of Oral Pirfenidone in Patients With Pulmonary Fibrosis/Idiopathic Pulmonary Fibrosis
NCT00109681	PHASE2	COMPLETED	Inhaled Iloprost in Adults With Abnormal Pulmonary Pressure and Associated With Idiopathic Pulmonary Fibrosis
NCT00352482	PHASE2	COMPLETED	Sildenafil to Increase Exercise Capacity in Individuals With Idiopathic Pulmonary Fibrosis and Pulmonary Hypertension
NCT00455767	PHASE2	COMPLETED	Safety and Efficacy Study of Depelestat in Acute Respiratory Distress Syndrome (ARDS) Patients
NCT00514683	PHASE2	COMPLETED	Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis
NCT00690885	PHASE2	TERMINATED	Interferon-alpha Treatment of Chronic Cough in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis
NCT00786201	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of CNTO 888 Administered Intravenously (IV) in Participants With Idiopathic Pulmonary Fibrosis (IPF)
NCT01135199	PHASE2	WITHDRAWN	Pomalidomide for Cough in Patients With Idiopathic Pulmonary Fibrosis
NCT01170065	PHASE2	COMPLETED	Roll Over Study From 1199.30 BIBF 1120 in Idiopathic Pulmonary Fibrosis (IPF)
NCT01203943	PHASE2	TERMINATED	A Study to Characterize the Safety, PK and Biological Activity of CC-930 in Idiopathic Pulmonary Fibrosis (IPF)
NCT01417156	PHASE2	COMPLETED	Safety and PK Study of BIBF 1120 in Japanese Patients With IPF: Follow up Study From 1199.31(NCT01136174)
NCT01442779	PHASE2	COMPLETED	Clinical Trial of Low Dose Oral Interferon Alpha in Idiopathic Pulmonary Fibrosis
NCT01917877	PHASE2	UNKNOWN	Efficiency Study for Acute Radiation-induced and Chemotherapy-induced Pulmonary Fibrosis With Bevasizumab
NCT02603068	PHASE2	WITHDRAWN	Oral Treprostinil in Subjects With Pulmonary Hypertension Associated With Pulmonary Fibrosis