COL4A1
protein-codingcollagen type IV alpha 1 chain, the group of Collagens
Gene summary
This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~158.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018786
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008289
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0800461
Submitter: ClinGen
COL4A1 codes for the collagen IV alpha 1 chain. This forms a heterotrimer (alpha1alpha1alpha2) and network with the collagen alpha 2 chain. This network is the major protein found in basement membranes in development and, later, in blood vessels as well as other basement membranes. COL4A1 was first reported associated with brain small vessel disease in 2005 by Gould et al. (PMID:15905400); and with Nephropathy (Hereditary Angiopathy with Nephropathy, Aneurysms and Muscle Cramps, HANAC) by Plaisier in 2007 (PMID:18160688). These rare diseases mainly result in brain infarcts but are also associated with haematuria, proteinuria and kidney cysts. Common brain features seen in affected probands include porencephaly, ventriculomegaly, schizencephaly, and leukoencephalopathy. The brain malformation phenotypes are typically present in fetal or neonatal-onset cases (PMIDs: 16107487, 25719457, 32732225, 33846711, 37486637). A similar overlapping spectrum is seen in cases of autosomal dominant COL4A2 variants. Per criteria outlined by the ClinGen Lumping and Splitting Working group, we found no difference in the molecular mechanisms or inheritance pattern between variants resulting in brain small vessel disease and HANAC or kidney cysts. Therefore both of these disease entities were lumped together into one. Many variants have been reported in COL4A1 but include mainly Gly missense substitutions in the intermediate collagenous domain as well as some truncating and splicing variants in many publications and databases. 10 variants (missense, nonsense, frameshift, splicing) that have been reported in at least 10 probands in 9 publications (PMIDs: 16107487, 18160688, 20733150, 20818663, 25719457, 27190376, 32515830, 36372235, 36922284) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease association is also supported by experimental evidence (biochemical function, protein interactions, expression studies, and non-human model organisms; PMIDs: 1635341, 18160688, 18219669, 26260163). Expression-level data indicates expression of the gene in the kidney blood vessels. Electron micrography shows that mutation of the COL4A1 gene leads to cerebral haemorrhage and kidney cysts. In a mouse model, COL4A1 homozygous mutants show lethality embryonically; both heterozygous and homozygous mutants have haemorrhages, retinal vessel tortuosity, albuminuria, haematuria, kidney cyts, as well as podocyte and glomerular basement membrane defects. In summary, COL4A1 is definitively associated with autosomal dominant COL4A1-related small vessel disease (and HANAC and kidney cysts). This has been reportedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Glomerulopathy GCEP on the meeting date 02/12/2024 (SOP Version 10). On 02/24/2026, the Brain Malformations GCEP added a secondary contribution to the evidence summary regarding the brain-related phenotypes. The classification did not change and no new evidence was added, so there is no change to the date last evaluated or SOP version.
Inheritance Pattern: AD
Disease ID:MONDO:0012726
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012726
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008289
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0000171
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008289
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012726
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0032814
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008373
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020496
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008289
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Cardiovascular; Ophthalmologic; Pharmacogenomic
Rationale: Trauma at birth and during adulthood, as well as issues such as hypertension and exercise-induced stress is a stronger risk factor for intracerebral hemorrhage than in persons without relevant variants; Anticoagulant use may exacerbate the stroke risk associated with COL4A1 variants; Individuals with Retinal artery tortuosity (isolated as part of a more syndromic context) have been described with transient vision loss because of retinal hemorrhage after minor stress (eg, exercise) or trauma, and knowledge may allow preventive measures to avoid retinal hemorrhage
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL4A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001845.6. 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 | 30 | 467 | 1 | 499 | |
| missense | 79 | 226 | 984 | 82 | 11 | 1382 |
| nonsense | 12 | 16 | 4 | 32 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 32 | 28 | 7 | 67 | ||
| splice donor/acceptor (+/-2bp) | 16 | 38 | 27 | 81 | ||
| Total | 141 | 310 | 1052 | 549 | 12 | 2064 |
Highest pathogenic variant AF is 0.00001982846
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001836.3 | 52 | MANE Select | |
| Ensembl | ENSP00000364979.4 | 52 | MANE Select | |
| RefSeq | NP_001290039.1 | 25 | Standard | |
| Ensembl | ENSP00000443348.1 | 25 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| col4a1 | Danio rerio | Structure: dorsal aorta Quality: increased elasticity abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Relaxin signaling pathway - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
Biological Process
- branching involved in blood vessel morphogenesis
- brain development
- neuromuscular junction development
- extracellular matrix organization
- epithelial cell differentiation
Molecular Function
- extracellular matrix structural constituent
- protein binding
- extracellular matrix structural constituent conferring tensile strength
- platelet-derived growth factor binding
Cellular Component
- extracellular region
- collagen type IV trimer
- basement membrane
- extracellular space
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375820
- Coding exons
- 52
- Length
- 158179
- Individuals with no LoFs
- 125728
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 125748
- p
- 0.0000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.02 | 701 | 965 | 0.726 | 0.0000550 | 10444 |
| Missense (PolyPhen) | 97 | 220.84 | 0.43923 | 2273 | ||
| Synonymous | -2.97 | 439 | 367 | 1.20 | 0.0000255 | 3662 |
| Loss of Function | 8.32 | 6 | 92.3 | 0.0650 | 0.00000473 | 1143 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen. {ECO:0000250|UniProtKB:P02463}.;
- Disease
- DISEASE: Brain small vessel disease with or without ocular anomalies (BSVD) [MIM:607595]: An autosomal dominant disease characterized by weakening of the blood vessels in the brain and retinal arteriolar tortuosity. In affected individuals, stroke is often the first symptom and is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke). Patients also have leukoencephalopathy and may experience seizures and migraine headaches accompanied by visual sensations known as auras. {ECO:0000269|PubMed:16598045, ECO:0000269|PubMed:17379824, ECO:0000269|PubMed:17696175, ECO:0000269|PubMed:19477666, ECO:0000269|PubMed:20385946, ECO:0000269|PubMed:22574627, ECO:0000269|PubMed:23394911, ECO:0000269|PubMed:24628545}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hereditary angiopathy with nephropathy aneurysms and muscle cramps (HANAC) [MIM:611773]: The clinical renal manifestations include hematuria and bilateral large cysts. Histologic analysis revealed complex basement membrane defects in kidney and skin. The systemic angiopathy appears to affect both small vessels and large arteries. {ECO:0000269|PubMed:18160688, ECO:0000269|PubMed:20818663}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Porencephaly 1 (POREN1) [MIM:175780]: A neurologic disorder characterized by a fluid-filled cysts or cavities within the cerebral hemispheres, neurologic manifestations, facial paresis, and visual defects. Affected individuals typically have hemiplegia, seizures, and intellectual disability. Porencephaly type 1 is usually unilateral and results from focal destructive lesions such as fetal vascular occlusion or birth trauma. {ECO:0000269|PubMed:15905400, ECO:0000269|PubMed:16107487, ECO:0000269|PubMed:19194877}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Intracerebral hemorrhage (ICH) [MIM:614519]: A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke. {ECO:0000269|PubMed:22522439}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Tortuosity of retinal arteries (RATOR) [MIM:180000]: A disease characterized by marked tortuosity of second- and third- order retinal arteries with normal first-order arteries and venous system. Most patients manifest variable degrees of symptomatic transient vision loss due to retinal hemorrhage following minor stress or trauma. {ECO:0000269|PubMed:25228067}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Schizencephaly (SCHZC) [MIM:269160]: Extremely rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. These clefts are lined with gray matter and most commonly involve the parasylvian regions. Large portions of the cerebral hemispheres may be absent and replaced by cerebro- spinal fluid. {ECO:0000269|PubMed:23225343}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.492
Intolerance Scores
- LoFtool
- 0.0123
- RVIS EVS
- -2.82
- RVIS percentile EVS
- 0.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.587
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | High | High |