SFTPA2
protein-codingsurfactant protein A2, the group of Collectins|C-type lectin domain containing
Gene summary
This gene is one of several genes encoding pulmonary-surfactant associated proteins (SFTPA) located on chromosome 10. Mutations in this gene and a highly similar gene located nearby, which affect the highly conserved carbohydrate recognition domain, are associated with idiopathic pulmonary fibrosis. The current version of the assembly displays only a single centromeric SFTPA gene pair rather than the two gene pairs shown in the previous assembly which were thought to have resulted from a duplication. [provided by RefSeq, Sep 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008345
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0800029
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0800029
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0008345
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0800497
Submitter: ClinGen
*SFTPA2* was first reported in relation to Interstitial Lung Disease (ILD), an autosomal dominant rare disease affecting the distal part of the lung, in 2009 (Wang et al., PMID:19100526). ILD can be described as a family of many lung disorders including idiopathic interstitial pneumonia (IIP) and pneumonitis to the more severe idiopathic pulmonary fibrosis (IPF). The most common phenotypes of ILD may include shortness of breath, cough, dyspnea, pulmonary fibrosis, and respiratory failure. Sixteen unique variants, all missense, have been reported in 22 probands across five publications (Legendre et al., 2020, PMID: 32855221; van Moorsel et al., 2015, PMID:26568241; Wang et al., 2009, PMID:19100526; Liu L, et al., 2020, PMID:32602668; Sutton et al., 2022, PMID:36135709). This gene-disease relationship is also supported by experimental evidence including an expression study that shows a high degree of specificity in the lung tissue (PMID:23715323). Other experimental evidence includes a biochemical function assay that explains how endoplasmic reticulum (ER) stress is associated with the development and progression of fibrotic diseases, including idiopathic pulmonary fibrosis (Burman et al., 2018, PMID:29567124). Functional alteration studies of variants in A549 cells and type II alveolar cells have been shown to lead to protein instability and increased ER stress (Maitra M et al., PMID: 20466729). In summary, there is definitive evidence supporting the relationship between *SFTPA2* and autosomal dominant ILD. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on June 20, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0800497
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Oncologic; Pulmonary
Intervention: Oncologic
Rationale: Surveillance for and early diagnosis of neoplasms could allow potentially beneficial treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SFTPA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001098668.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 15 | 4 | 20 | ||
| missense | 3 | 4 | 48 | 12 | 67 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 4 | 51 | 27 | 4 | 89 |
Highest pathogenic variant AF is 0.00018593235
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001092138.1 | 4 | MANE Select | |
| Ensembl | ENSP00000361400.2 | 4 | MANE Select | |
| RefSeq | NP_001307742.1 | 4 | Standard | |
| RefSeq | NP_001307743.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pertussis - Homo sapiens (human)
- Phagosome - Homo sapiens (human)
- Regulation of toll-like receptor signaling pathway
- Human Complement System
- Surfactant metabolism
Biological Process
- toll-like receptor signaling pathway
- respiratory gaseous exchange
- developmental process
- surfactant homeostasis
- cellular protein metabolic process
Molecular Function
- lipopolysaccharide binding
- monosaccharide binding
Cellular Component
- extracellular region
- collagen trimer
- extracellular space
- multivesicular body
- endoplasmic reticulum membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372325
- Coding exons
- 4
- Length
- 4546
- Individuals with no LoFs
- 125633
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 114
- Defined
- 125747
- p
- 0.000453
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.16 | 176 | 138 | 1.28 | 0.00000765 | 1578 |
| Missense (PolyPhen) | 59 | 50.613 | 1.1657 | 590 | ||
| Synonymous | -2.41 | 77 | 54.4 | 1.42 | 0.00000334 | 519 |
| Loss of Function | 1.10 | 4 | 7.18 | 0.557 | 3.09e-7 | 94 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00054 | 0.00054 | rare |
| Finnish | 0.0032 | 0.0032 | notable |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: In presence of calcium ions, it binds to surfactant phospholipids and contributes to lower the surface tension at the air-liquid interface in the alveoli of the mammalian lung and is essential for normal respiration.;
- Disease
- DISEASE: Pulmonary fibrosis, idiopathic (IPF) [MIM:178500]: A lung disease characterized by shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation and fibrosis on biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. {ECO:0000269|PubMed:19100526}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.137
Intolerance Scores
- LoFtool
- 0.523
- RVIS EVS
- 0.62
- RVIS percentile EVS
- 83.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.127
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |