COL4A4

collagen type IV alpha 4 chain, the group of Collagens

Basic information

Region (hg38): 2:227002713-227164453

Links

ENSG00000081052 ∙ NCBI:1286 ∙ OMIM:120131 ∙ HGNC:2206 ∙ Uniprot:P53420 ∙ 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 recessive Alport syndrome (Strong), mode of inheritance: AR
• autosomal recessive Alport syndrome (Definitive), mode of inheritance: AR
• hematuria, benign familial, 1 (Moderate), mode of inheritance: AD
• 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
• 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 2, 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; 7987396; 7783412; 8787673; 9195222; 20301386; 22166847; 22237748; 22811928; 22997344

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the COL4A4 gene.

• not provided (1891 variants)
• Alport syndrome (361 variants)
• Autosomal recessive Alport syndrome (302 variants)
• not specified (110 variants)
• Autosomal recessive Alport syndrome;Benign familial hematuria (100 variants)
• Benign familial hematuria;Autosomal recessive Alport syndrome (74 variants)
• Benign familial hematuria (66 variants)
• Autosomal dominant Alport syndrome (55 variants)
• Inborn genetic diseases (52 variants)
• COL4A4-related condition (39 variants)
• Kidney disorder (19 variants)
• Focal segmental glomerulosclerosis (11 variants)
• Autosomal dominant Alport syndrome;Benign familial hematuria (5 variants)
• Glomerulonephritis (4 variants)
• Microscopic hematuria (3 variants)
• Chronic kidney disease (3 variants)
• Atypical hemolytic-uremic syndrome (3 variants)
• Nephrotic syndrome (2 variants)
• Hypertensive disorder;Hyperkalemia;Stage 5 chronic kidney disease;Thrombocytopenia (1 variants)
• Steroid-resistant nephrotic syndrome (1 variants)
• See cases (1 variants)
• X-linked Alport syndrome (1 variants)
• COL4A4-related disorder (1 variants)
• Usher syndrome (1 variants)
• Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome (1 variants)
• Kidney damage (1 variants)
• Hypertensive disorder;Proteinuria;Hematuria;Hearing impairment;Myopia (1 variants)
• Myopia;Hearing impairment;Hypertensive disorder;Hematuria;Proteinuria (1 variants)
• Disease of glomerular basement membrane (1 variants)
• COL4A4-related disorders (1 variants)
• Hematuria (1 variants)
• Diffuse mesangial sclerosis (1 variants)
• Hypertensive disorder;Stage 5 chronic kidney disease;Hyperkalemia;Thrombocytopenia (1 variants)
• Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome;Benign familial hematuria (1 variants)
• Alport syndrome type 2 (1 variants)
• Hearing impairment (1 variants)
• Benign familial hematuria;Autosomal dominant Alport syndrome (1 variants)
• Autosomal recessive Alport syndrome;Alport syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the COL4A4 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			6	549	9	564
missense	19	72	331	51	12	485
nonsense	37	51	1			89
start loss						0
frameshift	95	73	2			170
inframe indel		6	9			15
splice donor/acceptor (+/-2bp)	12	77	3			92
splice region	1	2	36	119	4	162
non coding		1	113	299	156	569
Total	163	280	465	899	177

Highest pathogenic variant AF is 0.000105

Variants in COL4A4

This is a list of pathogenic ClinVar variants found in the COL4A4 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-227002723-G-C		Alport syndrome	Benign (Jan 13, 2018)
2-227002726-A-G		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227002742-T-C		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227002780-T-C		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227002791-A-G		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227002827-A-G		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227002830-G-GTCTT		Alport syndrome	Likely benign (Jun 14, 2016)
2-227002932-C-A		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227002940-T-C		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227002956-G-A		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227002962-C-G		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227002978-G-A		Alport syndrome	Uncertain significance (Jan 12, 2018)
2-227003003-G-A		Alport syndrome	Benign (Jan 12, 2018)
2-227003131-G-A		Alport syndrome	Conflicting classifications of pathogenicity (Mar 01, 2023)
2-227003152-T-A		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227003161-G-A		Alport syndrome	Likely benign (Jan 13, 2018)
2-227003190-T-A		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227003219-G-T		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227003222-T-TA		Alport syndrome	Uncertain significance (Jun 14, 2016)
2-227003284-T-C		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227003319-CTT-C		Alport syndrome	Uncertain significance (Jun 14, 2016)
2-227003377-G-A		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227003385-A-G		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227003387-T-C		Alport syndrome	Uncertain significance (Jan 13, 2018)
2-227003449-C-T		Alport syndrome	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
COL4A4	protein_coding	protein_coding	ENST00000396625	47	161403

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.71e-16	1.00	124700	0	94	124794	0.000377

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.02	874	963	0.908	0.0000504	10509
Missense in Polyphen		220	244.17	0.90102		2513
Synonymous	-1.18	373	345	1.08	0.0000197	3775
Loss of Function	4.49	40	84.5	0.473	0.00000387	1113

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000790	0.000778
Ashkenazi Jewish	0.000199	0.000199
East Asian	0.000279	0.000278
Finnish	0.0000465	0.0000464
European (Non-Finnish)	0.000470	0.000459
Middle Eastern	0.000279	0.000278
South Asian	0.000459	0.000458
Other	0.000495	0.000495

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: 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:7987396, ECO:0000269|PubMed:9792860}. 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, ECO:0000269|PubMed:12631110, ECO:0000269|PubMed:8787673}. 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;Focal Adhesion;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;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: 0.249

Intolerance Scores

• loftool: 0.0825
• rvis_EVS: 1.04
• rvis_percentile_EVS: 91.27

Haploinsufficiency Scores

• pHI: 0.0981
• hipred: N
• hipred_score: 0.474
• ghis: 0.437

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0237

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Col4a4
• Phenotype: homeostasis/metabolism phenotype; growth/size/body region phenotype; immune system phenotype; renal/urinary system phenotype; digestive/alimentary phenotype; hearing/vestibular/ear 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: angiogenesis;endothelial cell morphogenesis;extracellular matrix organization;glomerular basement membrane development
• Cellular component: extracellular region;collagen type IV trimer;basement membrane;extracellular space;endoplasmic reticulum lumen;extracellular matrix
• Molecular function: extracellular matrix structural constituent