COL4A1

collagen type IV alpha 1 chain, the group of Collagens

Basic information

Region (hg38): 13:110148963-110307202

Links

ENSG00000187498 ∙ NCBI:1282 ∙ OMIM:120130 ∙ HGNC:2202 ∙ Uniprot:P02462 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• brain small vessel disease 1 with or without ocular anomalies (Strong), mode of inheritance: AD
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (Strong), mode of inheritance: AD
• brain small vessel disease 1 with or without ocular anomalies (Strong), mode of inheritance: AD
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (Moderate), mode of inheritance: AD
• brain small vessel disease 1 with or without ocular anomalies (Moderate), mode of inheritance: AD
• muscular dystrophy-dystroglycanopathy, type A (Supportive), mode of inheritance: AR
• brain small vessel disease 1 with or without ocular anomalies (Supportive), mode of inheritance: AD
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (Supportive), mode of inheritance: AD
• retinal arterial tortuosity (Supportive), mode of inheritance: AD
• familial porencephaly (Supportive), mode of inheritance: AD
• pontine autosomal dominant microangiopathy with leukoencephalopathy (Supportive), mode of inheritance: AD
• brain small vessel disease 1 with or without ocular anomalies (Definitive), mode of inheritance: AD
• microangiopathy and leukoencephalopathy, pontine, autosomal dominant (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant; Brain small vessel disease 1 with or without ocular anomalies; Anterior segment dysgenesis with cerebral involvement; Retinal artery tortuosity	AD	Cardiovascular; Ophthalmologic; Pharmacogenomic	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	Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic; Renal	6428250; 12525718; 15136694; 15905400; 15882279; 17030722; 16598045; 18160688; 17696175; 19949034; 19194877; 20056676; 22522439; 23225343; 23394911; 24628545; 25228067; 25719457; 27666438; 28017902

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the COL4A1 gene.

• not provided (55 variants)
• Brain small vessel disease 1 with or without ocular anomalies (19 variants)
• Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (6 variants)
• Inborn genetic diseases (4 variants)
• Microangiopathy and leukoencephalopathy, pontine, autosomal dominant (3 variants)
• Cerebral palsy (1 variants)
• COL4A1-related disorder (1 variants)
• Intraventricular hemorrhage;Abnormal corpus callosum morphology (1 variants)
• See cases (1 variants)
• Cerebral calcification;Intracranial hemorrhage (1 variants)
• Porencephaly (1 variants)
• COL4A1 or COL4A2-related cerebral small vessel disease (1 variants)
• Optic nerve hypoplasia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the COL4A1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			13	331	10	354
missense	43	130	630	27	8	838
nonsense	4	7	1			12
start loss	1	1				2
frameshift	20	7				27
inframe indel		4	5			9
splice donor/acceptor (+/-2bp)	11	22	5			38
splice region			57	97	8	162
non coding	1	1	31	332	192	557
Total	80	172	685	690	210

Highest pathogenic variant AF is 0.00000657

Variants in COL4A1

This is a list of pathogenic ClinVar variants found in the COL4A1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
13-110149264-C-T		Porencephalic cyst • Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Conflicting classifications of pathogenicity (Jan 13, 2018)
13-110149324-T-C		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jan 13, 2018)
13-110149349-G-A		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Benign/Likely benign (Jan 13, 2018)
13-110149368-G-A		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jan 13, 2018)
13-110149388-T-G		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Benign/Likely benign (Jan 12, 2018)
13-110149411-T-C		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Mar 16, 2018)
13-110149475-GT-G		Porencephalic cyst • Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jun 14, 2016)
13-110149525-A-G		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Benign (Jan 13, 2018)
13-110149597-C-T		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Porencephalic cyst • Brain small vessel disease 1 with or without ocular anomalies	Benign/Likely benign (Jan 12, 2018)
13-110149715-A-AAT		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Porencephalic cyst • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jun 14, 2016)
13-110149754-A-G		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Benign/Likely benign (Jan 12, 2018)
13-110149776-G-T		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Porencephalic cyst • Brain small vessel disease 1 with or without ocular anomalies	Benign (Jan 13, 2018)
13-110149832-A-T		Porencephalic cyst • Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jan 13, 2018)
13-110149833-T-C		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jan 12, 2018)
13-110149853-T-C		Porencephalic cyst • Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jan 13, 2018)
13-110149886-C-A		Porencephalic cyst • Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jan 13, 2018)
13-110149930-A-C		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies	Uncertain significance (Jan 13, 2018)
13-110150098-T-C		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Porencephalic cyst • Brain small vessel disease 1 with or without ocular anomalies	Conflicting classifications of pathogenicity (Jan 12, 2018)
13-110150187-T-C		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Porencephalic cyst • Brain small vessel disease 1 with or without ocular anomalies	Benign/Likely benign (Jan 12, 2018)
13-110150226-C-T		Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome • Brain small vessel disease 1 with or without ocular anomalies • Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome;Brain small vessel disease 1 with or without ocular anomalies;Hemorrhage, intracerebral, susceptibility to;Microangiopathy and leukoencephalopathy, pontine, autosomal dominant;Retinal arterial tortuosity	Uncertain significance (Feb 01, 2022)
13-110150327-A-T		Vascular dementia	Uncertain significance (Oct 01, 2021)
13-110150327-AG-A			Uncertain significance (Jan 12, 2022)
13-110150328-G-T		Microangiopathy and leukoencephalopathy, pontine, autosomal dominant	Pathogenic (Sep 06, 2019)
13-110150331-C-A		Microangiopathy and leukoencephalopathy, pontine, autosomal dominant	Pathogenic (Oct 13, 2023)
13-110150331-C-T		Microangiopathy and leukoencephalopathy, pontine, autosomal dominant • Brain small vessel disease 1 with or without ocular anomalies	Likely pathogenic (Sep 22, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
COL4A1	protein_coding	protein_coding	ENST00000375820	52	158179

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.62e-11	125728	0	20	125748	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.02	701	965	0.726	0.0000550	10444
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000141	0.000141
Middle Eastern	0.000163	0.000163
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Small cell lung cancer - Homo sapiens (human);Protein digestion and absorption - Homo sapiens (human);Amoebiasis - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;Spinal Cord Injury;miRNA targets in ECM and membrane receptors;Focal Adhesion;Overview of nanoparticle effects;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Protein alkylation leading to liver fibrosis;PI3K-Akt Signaling Pathway;EMT transition in Colorectal Cancer;Developmental Biology;Assembly of collagen fibrils and other multimeric structures;Signal Transduction;regulators of bone mineralization;Vesicle-mediated transport;intrinsic prothrombin activation pathway;Collagen chain trimerization;Collagen biosynthesis and modifying enzymes;Integrin cell surface interactions;Signaling by PDGF;Collagen formation;Extracellular matrix organization;Beta3 integrin cell surface interactions;Integrin;NCAM signaling for neurite out-growth;NCAM1 interactions;Axon guidance;Binding and Uptake of Ligands by Scavenger Receptors;Signaling by Receptor Tyrosine Kinases;Scavenging by Class A Receptors;Beta1 integrin cell surface interactions;Syndecan-1-mediated signaling events;Integrins in angiogenesis (Consensus)

Recessive Scores

• pRec: 0.492

Intolerance Scores

• loftool: 0.0123
• rvis_EVS: -2.82
• rvis_percentile_EVS: 0.62

Haploinsufficiency Scores

• pHI: 0.853
• hipred: Y
• hipred_score: 0.733
• ghis: 0.679

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.587

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Col4a1
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; immune system phenotype; renal/urinary system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: col4a1
• Affected structure: dorsal aorta
• Phenotype tag: abnormal
• Phenotype quality: increased elasticity

Gene ontology

• Biological process: branching involved in blood vessel morphogenesis;brain development;neuromuscular junction development;extracellular matrix organization;epithelial cell differentiation;collagen-activated tyrosine kinase receptor signaling pathway;blood vessel morphogenesis;retinal blood vessel morphogenesis;renal tubule morphogenesis;cellular response to amino acid stimulus;basement membrane organization
• Cellular component: extracellular region;collagen type IV trimer;basement membrane;extracellular space;endoplasmic reticulum lumen;extracellular matrix;collagen-containing extracellular matrix
• Molecular function: extracellular matrix structural constituent;protein binding;extracellular matrix structural constituent conferring tensile strength;platelet-derived growth factor binding