COL4A3

collagen type IV alpha 3 chain, the group of Collagens

Basic information

Region (hg38): 2:227164623-227314792

Links

ENSG00000169031 ∙ NCBI:1285 ∙ OMIM:120070 ∙ HGNC:2204 ∙ Uniprot:Q01955 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive Alport syndrome (Definitive), mode of inheritance: AR
• autosomal recessive Alport syndrome (Definitive), mode of inheritance: AR
• hematuria, benign familial, 1 (Strong), mode of inheritance: AD
• autosomal dominant Alport syndrome (Strong), mode of inheritance: AD
• autosomal recessive Alport syndrome (Strong), mode of inheritance: AR
• autosomal dominant Alport syndrome (Supportive), mode of inheritance: AD
• autosomal recessive Alport syndrome (Supportive), mode of inheritance: AR
• autosomal recessive Alport syndrome (Strong), mode of inheritance: AR
• autosomal recessive Alport syndrome (Strong), mode of inheritance: AR
• autosomal dominant Alport syndrome (Definitive), mode of inheritance: AD
• hematuria, benign familial, 1 (Strong), mode of inheritance: AD
• Alport syndrome (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alport syndrome 3A, autosomal dominant; Alport syndrome 3B, autosomal recessive	AD/AR	Ophthalmologic; Renal	In Alport syndrome, medical treatment related to renal sequelae (eg, with ACE inhibitors, ARBs) may be beneficial related to delaying renal failure, as well as with overall life expectancy, though dialysis/renal transplantation may be required; Corneal protection may be beneficial in individuals with recurrent corneal erosions	Audiologic/Otolaryngologic; Ophthalmologic; Renal	7033680; 7987301; 8196274; 7987396; 7783412; 7783419; 9195222; 9269635; 11961012; 11134255; 20301386; 22166847; 22237748; 22811928; 22997344; 23927549

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the COL4A3 gene.

• not provided (1721 variants)
• Autosomal recessive Alport syndrome (307 variants)
• Alport syndrome (291 variants)
• Autosomal dominant Alport syndrome (138 variants)
• not specified (122 variants)
• Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome;Benign familial hematuria (65 variants)
• Inborn genetic diseases (42 variants)
• Benign familial hematuria;Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome (34 variants)
• COL4A3-related condition (33 variants)
• Autosomal dominant Alport syndrome;Benign familial hematuria;Autosomal recessive Alport syndrome (29 variants)
• Autosomal recessive Alport syndrome;Autosomal dominant Alport syndrome;Benign familial hematuria (19 variants)
• Kidney disorder (12 variants)
• Benign familial hematuria (12 variants)
• Benign familial hematuria;Autosomal recessive Alport syndrome;Autosomal dominant Alport syndrome (11 variants)
• Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome (9 variants)
• Focal segmental glomerulosclerosis (5 variants)
• Hearing impairment (4 variants)
• Autosomal dominant Alport syndrome;Benign familial hematuria (4 variants)
• Atypical hemolytic-uremic syndrome (4 variants)
• COL4A3-Related Disorders (3 variants)
• Chronic kidney disease (3 variants)
• - (3 variants)
• Hematuria (2 variants)
• Autosomal recessive Alport syndrome;Autosomal dominant Alport syndrome (2 variants)
• Nephrotic syndrome (2 variants)
• Autosomal recessive Alport syndrome;Benign familial hematuria;Autosomal dominant Alport syndrome (2 variants)
• Steroid-resistant nephrotic syndrome (1 variants)
• Proteinuria;Moderate albuminuria;Microscopic hematuria (1 variants)
• See cases (1 variants)
• Stickler syndrome (1 variants)
• Hereditary disease (1 variants)
• Microscopic hematuria (1 variants)
• Alport syndrome 3b, autosomal recessive (1 variants)
• Hematuria;Glomerulopathy (1 variants)
• focal and segmental glomerulosclerosis (1 variants)
• Benign familial hematuria;Autosomal dominant Alport syndrome (1 variants)
• Macroscopic hematuria (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the COL4A3 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			9	460	3	472
missense	25	92	312	44	12	485
nonsense	38	55	1			94
start loss	1	2				3
frameshift	74	59	2			135
inframe indel	2	6	13	1		22
splice donor/acceptor (+/-2bp)	18	81		1		100
splice region	1	1	20	119	7	148
non coding		1	51	247	143	442
Total	158	296	388	753	158

Highest pathogenic variant AF is 0.0000527

Variants in COL4A3

This is a list of pathogenic ClinVar variants found in the COL4A3 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-227164646-G-C		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227164701-G-T		Alport syndrome	Conflicting classifications of pathogenicity (Jun 07, 2018)
2-227164711-T-C		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227164714-G-C		Alport syndrome • not specified	Conflicting classifications of pathogenicity (Mar 09, 2018)
2-227164717-C-T		Alport syndrome • not specified • Autosomal dominant Alport syndrome • COL4A3-related disorder	Conflicting classifications of pathogenicity (Dec 18, 2023)
2-227164727-A-C		Autosomal recessive Alport syndrome	Pathogenic/Likely pathogenic (Jun 14, 2022)
2-227164727-A-G			Pathogenic (Oct 31, 2022)
2-227164728-T-C		Autosomal recessive Alport syndrome	Likely pathogenic (Mar 07, 2018)
2-227164732-C-T			Likely benign (Dec 09, 2023)
2-227164737-G-A		Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome;Benign familial hematuria	Uncertain significance (Mar 17, 2023)
2-227164738-G-T			Likely benign (May 20, 2023)
2-227164741-C-A			Likely benign (Apr 10, 2023)
2-227164741-C-G			Likely benign (Aug 06, 2022)
2-227164741-C-T			Likely benign (Mar 24, 2021)
2-227164742-G-T		not specified	Uncertain significance (Nov 02, 2022)
2-227164743-C-A			Uncertain significance (Dec 14, 2023)
2-227164744-C-T			Likely benign (Jun 20, 2023)
2-227164747-C-A		not specified • Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome;Benign familial hematuria	Likely benign (Jan 29, 2024)
2-227164747-C-T			Likely benign (Dec 29, 2023)
2-227164748-A-C			Likely benign (Jul 25, 2023)
2-227164751-C-T		Autosomal dominant Alport syndrome;Benign familial hematuria;Autosomal recessive Alport syndrome	Conflicting classifications of pathogenicity (Jan 05, 2024)
2-227164752-C-T		not specified	Uncertain significance (Dec 13, 2023)
2-227164753-G-A			Likely benign (Dec 05, 2023)
2-227164753-G-C			Likely benign (Dec 09, 2021)
2-227164753-G-T			Likely benign (Nov 29, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
COL4A3	protein_coding	protein_coding	ENST00000396578	52	150228

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.07e-12	1.00	124648	0	146	124794	0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.99	763	935	0.816	0.0000484	10352
Missense in Polyphen		144	201.02	0.71635		2111
Synonymous	0.537	315	327	0.962	0.0000186	3697
Loss of Function	5.45	38	95.4	0.398	0.00000489	1208

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00157	0.00157
Ashkenazi Jewish	0.000199	0.000199
East Asian	0.000392	0.000389
Finnish	0.000279	0.000278
European (Non-Finnish)	0.000533	0.000530
Middle Eastern	0.000392	0.000389
South Asian	0.000761	0.000752
Other	0.000831	0.000825

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.
• Disease: DISEASE: Note=Autoantibodies against the NC1 domain of alpha 3(IV) are found in Goodpasture syndrome, an autoimmune disease of lung and kidney.; DISEASE: Alport syndrome, autosomal recessive (APSAR) [MIM:203780]: A syndrome characterized by progressive glomerulonephritis, glomerular basement membrane defects, renal failure, sensorineural deafness and specific eye abnormalities (lenticonous and macular flecks). The disorder shows considerable heterogeneity in that families differ in the age of end-stage renal disease and the occurrence of deafness. {ECO:0000269|PubMed:11134255, ECO:0000269|PubMed:15954103, ECO:0000269|PubMed:29946535}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hematuria, benign familial (BFH) [MIM:141200]: An autosomal dominant condition characterized by non-progressive isolated microscopic hematuria that does not result in renal failure. It is characterized pathologically by thinning of the glomerular basement membrane. {ECO:0000269|PubMed:11961012}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alport syndrome, autosomal dominant (APSAD) [MIM:104200]: A syndrome characterized by progressive glomerulonephritis, glomerular basement membrane defects, renal failure, sensorineural deafness and specific eye abnormalities (lenticonous and macular flecks). The disorder shows considerable heterogeneity in that families differ in the age of end-stage renal disease and the occurrence of deafness. {ECO:0000269|PubMed:11044206, ECO:0000269|PubMed:11134255}. 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;Primary Focal Segmental Glomerulosclerosis FSGS;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;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;Signaling by Receptor Tyrosine Kinases;Beta1 integrin cell surface interactions;Syndecan-1-mediated signaling events;Integrins in angiogenesis (Consensus)

Recessive Scores

• pRec: 0.340

Intolerance Scores

• loftool: 0.0989
• rvis_EVS: 1.35
• rvis_percentile_EVS: 94.31

Haploinsufficiency Scores

• pHI: 0.292
• hipred: Y
• hipred_score: 0.575
• ghis: 0.415

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.461

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Col4a3
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); hematopoietic system 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)

Gene ontology

• Biological process: activation of cysteine-type endopeptidase activity involved in apoptotic process;cell adhesion;cell surface receptor signaling pathway;sensory perception of sound;blood circulation;cell population proliferation;negative regulation of cell population proliferation;response to glucose;negative regulation of endopeptidase activity;negative regulation of angiogenesis;extracellular matrix organization;glomerular basement membrane development;collagen-activated tyrosine kinase receptor signaling pathway;endothelial cell apoptotic process
• Cellular component: extracellular region;collagen type IV trimer;basement membrane;extracellular space;endoplasmic reticulum;endoplasmic reticulum lumen;extracellular matrix;intracellular membrane-bounded organelle;collagen-containing extracellular matrix
• Molecular function: integrin binding;structural molecule activity;extracellular matrix structural constituent;protein binding;metalloendopeptidase inhibitor activity;extracellular matrix structural constituent conferring tensile strength