COL4A6

Summary

COL4A6 (collagen type IV alpha 6 chain, HGNC:2208) is a protein-coding gene on chromosome Xq22.3, encoding Collagen alpha-6(IV) chain (Q14031). 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.

This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene, alpha 5 type IV collagen, so that the gene pair shares a common promoter. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1288 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, X-linked 6 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 905 total — 5 likely-pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes
• MANE Select transcript: NM_033641

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2208
Approved symbol	COL4A6
Name	collagen type IV alpha 6 chain
Location	Xq22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197565
Ensembl biotype	protein_coding
OMIM	303631
Entrez	1288

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000334504, ENST00000372216, ENST00000394872, ENST00000461897, ENST00000468338, ENST00000477085, ENST00000487645, ENST00000538570, ENST00000621266, ENST00000913234, ENST00000913235, ENST00000913236, ENST00000962005

RefSeq mRNA: 5 — MANE Select: NM_033641 NM_001287758, NM_001287759, NM_001287760, NM_001847, NM_033641

CCDS: CCDS14541, CCDS14542, CCDS76008, CCDS76009, CCDS76010

Canonical transcript exons

ENST00000334504 — 45 exons

Exon	Start	End
ENSE00000866569	108175654	108175797
ENSE00000866570	108176841	108177011
ENSE00000866571	108179217	108179438
ENSE00000907950	108178684	108178845
ENSE00001033217	108159462	108159748
ENSE00001033224	108193628	108193697
ENSE00001033236	108214112	108214228
ENSE00001033241	108187848	108188027
ENSE00001033243	108169495	108169620
ENSE00001033247	108164600	108164698
ENSE00001033249	108211672	108211740
ENSE00001033252	108162892	108163038
ENSE00001033264	108169945	108170016
ENSE00001033265	108188517	108188677
ENSE00001033277	108160463	108160654
ENSE00001033284	108165370	108165486
ENSE00001033303	108175090	108175215
ENSE00001338885	108170609	108170716
ENSE00001338894	108180515	108180622
ENSE00001363319	108190392	108190496
ENSE00001363322	108191393	108191533
ENSE00001363325	108192473	108192580
ENSE00001363336	108196511	108196579
ENSE00001363342	108202928	108202981
ENSE00001370969	108170810	108170917
ENSE00001373205	108164877	108165038
ENSE00001379459	108161619	108161735
ENSE00001390469	108187096	108187279
ENSE00001409495	108206518	108206580
ENSE00001415660	108180897	108180968
ENSE00001416085	108174440	108174621
ENSE00001419008	108171387	108171461
ENSE00001421246	108172469	108172532
ENSE00001434706	108205660	108205695
ENSE00001435300	108209969	108210004
ENSE00001435608	108195082	108195126
ENSE00001435661	108194534	108194587
ENSE00001435991	108204320	108204412
ENSE00001436329	108205439	108205480
ENSE00003515098	108310748	108310828
ENSE00003515731	108437942	108437993
ENSE00003535545	108221240	108221374
ENSE00003690371	108219698	108219742
ENSE00003896830	108155614	108157260
ENSE00003896972	108438186	108438422

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 98.61.

FANTOM5 (CAGE): breadth broad, TPM avg 10.2107 / max 326.3386, expressed in 733 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200100	8.2780	661
200101	0.9486	275
200102	0.4090	215
200097	0.1877	76
200099	0.1815	111
200098	0.1529	95
200096	0.0531	18

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	98.61	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.19	gold quality
lower esophagus	UBERON:0013473	97.07	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.30	gold quality
ventricular zone	UBERON:0003053	94.76	gold quality
seminal vesicle	UBERON:0000998	93.29	gold quality
urethra	UBERON:0000057	91.92	gold quality
urinary bladder	UBERON:0001255	91.49	gold quality
body of uterus	UBERON:0009853	91.18	gold quality
left uterine tube	UBERON:0001303	89.57	gold quality
mucosa of urinary bladder	UBERON:0001259	88.82	gold quality
cauda epididymis	UBERON:0004360	88.15	gold quality
decidua	UBERON:0002450	87.37	gold quality
myometrium	UBERON:0001296	86.90	gold quality
gall bladder	UBERON:0002110	86.55	gold quality
tibial artery	UBERON:0007610	86.22	gold quality
popliteal artery	UBERON:0002250	86.21	gold quality
blood vessel layer	UBERON:0004797	84.33	gold quality
ganglionic eminence	UBERON:0004023	83.56	gold quality
fundus of stomach	UBERON:0001160	83.52	gold quality
caput epididymis	UBERON:0004358	83.39	gold quality
corpus epididymis	UBERON:0004359	83.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.88	gold quality
ectocervix	UBERON:0012249	82.83	gold quality
prostate gland	UBERON:0002367	82.48	gold quality
endocervix	UBERON:0000458	81.57	gold quality
esophagus	UBERON:0001043	81.05	gold quality
right ovary	UBERON:0002118	80.56	gold quality
smooth muscle tissue	UBERON:0001135	80.52	gold quality
saphenous vein	UBERON:0007318	80.09	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.84
E-MTAB-7249	yes	2.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

91 targeting COL4A6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-96-5P	99.95	72.80	2140

Literature-anchored findings (GeneRIF, showing 21)

• We provide a first indication that highly specialized patterns characteristic of COL4A5-COL4A6 expression in vivo arise from effects of distributed cis-acting regulatory elements on a bidirectional proximal promoter, itself transcriptionally competent. (PMID:14592452)
• Collagen chains alpha5(IV) and alpha6(IV) were frequently absent in basement membrane from pancreatic adenocarcinoma, and their absence might be related to the invasion of cancer cells. (PMID:15211113)
• Enhanced expression of collagen type IV is associated with liver metastases from gastrointestinal tumours (PMID:15679046)
• The expression of the alpha5(IV)/alpha6(IV) chains was down-regulated in colorectal cancer, and the loss of expression of the alpha5(IV)/alpha6(IV) chains was associated with the hypermethylation of their promoter region. (PMID:16507901)
• This study showed that in some cases of esophageal squamous cell carcinoma the alpha5/alpha6 (IV) chains are expressed linearly around the cancer cell nests and the alpha5/alpha6 (IV) chain expression is one prognostic factor of ESCC. (PMID:17955302)
• Type IV collagen alpha6 chain-derived noncollagenous domain 1 (alpha6NC1) is an endogenous inhibitor of angiogenesis and tumor growth. (PMID:18074349)
• Meningiomas increase in size through increased production of extracellular matrix; furthermore, the proliferation of cells typically associated with neoplasia requires considerable interaction with the extracellular matrix. (PMID:18474427)
• The expression of collagen type IV was significantly decreased in colorectal cancer tissues. (PMID:18782525)
• Results suggest that the down-regulation of alpha 6(IV) mRNA coincides with the acquisition of invasive growth properties, whereas alpha1(IV) and alpha1(VII) mRNAs were up-regulated already in dysplastic tissue. (PMID:19422682)
• The expression of Col I, Col IV and Fn was closely related to tumor invasion, the regional lymph node metastasis and other pathological features in laryngeal squamous cell carcinoma. (PMID:20359090)
• expression of collagen type IV alpha6 chain in the smooth muscle BM of the gastrointestinal tract is restricted to the esophagus in humans (PMID:20951201)
• In this paper we improve the definition of the COL4A5/COL4A6 deletions in three Alport syndrome with diffuse leiomyomatosis. (PMID:21380622)
• The expression of collagen type IV and its alpha chains (alpha1-6) was investigated in different endothelial cell culture systems in vitro qualitatively and quantitatively. (PMID:23551189)
• We showed that TPM2, CLU, and COL4A6 mRNA levels are downregulated in prostate cancer. (PMID:23621580)
• COL4A6 is associated with X-linked nonsyndromic hearing loss. (PMID:23714752)
• New deletion in COL4A6/COL4A5 related to diffuse esophageal leiomyomatosis associated with Alport syndrome in a Chinese family. (PMID:26179878)
• Mutation in COL4A6 gene is associated with gastric cancer peritoneal carcinomatosis. (PMID:26811494)
• although alpha5 and alpha6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role (PMID:27377778)
• deletion breakpoints in five Alport syndrome-diffuse leiomyomatosis patients and show a contiguous COL4A6/COL4A5 deletion in each case, were characterized. (PMID:28275241)
• These findings indicate that alpha112:alpha556 (IV) network, which is the only network that includes the alpha6(IV) chain, is one regulator of KRT10 expression in keratinization of oral mucosal epithelium. (PMID:29422532)
• Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications. (PMID:33840813)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Col4a6	ENSMUSG00000031273
rattus_norvegicus	Col4a6	ENSRNOG00000056772
drosophila_melanogaster	vkg	FBGN0016075
caenorhabditis_elegans		WBGENE00001263

Paralogs (37): COL9A2 (ENSG00000049089), COL23A1 (ENSG00000050767), COL11A1 (ENSG00000060718), COL17A1 (ENSG00000065618), COL5A3 (ENSG00000080573), COL4A4 (ENSG00000081052), COL16A1 (ENSG00000084636), COL9A3 (ENSG00000092758), COL20A1 (ENSG00000101203), COL1A1 (ENSG00000108821), COL9A1 (ENSG00000112280), COL7A1 (ENSG00000114270), COL21A1 (ENSG00000124749), COL5A1 (ENSG00000130635), COL4A2 (ENSG00000134871), COL2A1 (ENSG00000139219), COL6A1 (ENSG00000142156), COL6A2 (ENSG00000142173), EDA (ENSG00000158813), COL26A1 (ENSG00000160963), COL1A2 (ENSG00000164692), COL3A1 (ENSG00000168542), COL4A3 (ENSG00000169031), COL22A1 (ENSG00000169436), COL24A1 (ENSG00000171502), COL18A1 (ENSG00000182871), EMID1 (ENSG00000186998), COL4A1 (ENSG00000187498), COL4A5 (ENSG00000188153), COL25A1 (ENSG00000188517), COL27A1 (ENSG00000196739), COL13A1 (ENSG00000197467), COL11A2 (ENSG00000204248), COL5A2 (ENSG00000204262), COL15A1 (ENSG00000204291), COLQ (ENSG00000206561), COL28A1 (ENSG00000215018)

Protein

Protein identifiers

Collagen alpha-6(IV) chain — Q14031 (reviewed: Q14031)

All UniProt accessions (4): A0A087WZY5, A8MXH5, Q14031, F5H3Q5

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. There are six type IV collagen isoforms, alpha 1(IV)-alpha 6(IV), each of which can form a triple helix structure with 2 other chains to generate type IV collagen network.

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Basement membrane.

Post-translational modifications. Prolines at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains. Type IV collagens contain numerous cysteine residues which are involved in inter- and intramolecular disulfide bonding. 12 of these, located in the NC1 domain, are conserved in all known type IV collagens. The trimeric structure of the NC1 domains is stabilized by covalent bonds between Lys and Met residues.

Disease relevance. Deletions covering the N-terminal regions of COL4A5 and COL4A6, which are localized in a head-to-head manner, are found in the chromosome Xq22.3 centromeric deletion syndrome. This results in a phenotype with features of diffuse leiomyomatosis and Alport syndrome (DL-ATS). Deafness, X-linked, 6 (DFNX6) [MIM:300914] A non-syndromic form of sensorineural hearing loss with prelingual onset. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Alpha chains of type IV collagen have a non-collagenous domain (NC1) at their C-terminus, frequent interruptions of the G-X-Y repeats in the long central triple-helical domain (which may cause flexibility in the triple helix), and a short N-terminal triple-helical 7S domain.

Similarity. Belongs to the type IV collagen family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14031-1	A	yes
Q14031-2	B

RefSeq proteins (5): NP_001274687, NP_001274688, NP_001274689, NP_001838, NP_378667* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001442	Collagen_IV_NC	Domain
IPR008160	Collagen	Repeat
IPR016187	CTDL_fold	Homologous_superfamily
IPR036954	Collagen_IV_NC_sf	Homologous_superfamily
IPR050149	Collagen_superfamily	Family

Pfam: PF01391, PF01413

UniProt features (59 total): compositionally biased region 22, sequence variant 8, sequence conflict 8, region of interest 7, disulfide bond 6, short sequence motif 3, signal peptide 1, chain 1, domain 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14031-F1	48.27	0.12

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (6): 1482–1571, 1515–1568, 1527–1533, 1590–1687, 1624–1684, 1636–1643

Glycosylation sites (1): 127

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1566977	Fibronectin matrix formation
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-216083	Integrin cell surface interactions
R-HSA-2214320	Anchoring fibril formation
R-HSA-2243919	Crosslinking of collagen fibrils
R-HSA-3000157	Laminin interactions
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-8948216	Collagen chain trimerization
R-HSA-9638630	Attachment of bacteria to epithelial cells
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371511	HSF1 activation
R-HSA-3371568	Attenuation phase
R-HSA-3371571	HSF1-dependent transactivation

MSigDB gene sets: 310 (showing top): BROWNE_HCMV_INFECTION_4HR_UP, LEE_NEURAL_CREST_STEM_CELL_DN, BENPORATH_ES_WITH_H3K27ME3, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_RESPONSE_TO_ACID_CHEMICAL, JAEGER_METASTASIS_DN, GOCC_COLLAGEN_TRIMER, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, HNF1_Q6, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, AAAYRNCTG_UNKNOWN, BRUECKNER_TARGETS_OF_MIRLET7A3_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1

GO Biological Process (5): cell adhesion (GO:0007155), collagen fibril organization (GO:0030199), collagen-activated tyrosine kinase receptor signaling pathway (GO:0038063), cellular response to amino acid stimulus (GO:0071230), extracellular matrix organization (GO:0030198)

GO Molecular Function (3): extracellular matrix structural constituent conferring tensile strength (GO:0030020), extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), collagen type IV trimer (GO:0005587), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), collagen trimer (GO:0005581), basement membrane (GO:0005604)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Extracellular matrix organization	5
Cellular response to heat stress	3
Collagen formation	2
Assembly of collagen fibrils and other multimeric structures	2
Degradation of the extracellular matrix	1
Collagen biosynthesis and modifying enzymes	1
Biofilm formation	1
HSF1-dependent transactivation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular matrix	2
cellular process	1
extracellular matrix organization	1
cell surface receptor protein tyrosine kinase signaling pathway	1
collagen-activated signaling pathway	1
response to amino acid	1
cellular response to acid chemical	1
extracellular structure organization	1
external encapsulating structure organization	1
extracellular matrix structural constituent	1
structural molecule activity	1
binding	1
cellular anatomical structure	1
network-forming collagen trimer	1
chicken-wire-like collagen network	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL4A6	MID2	Q9UJV3	760
COL4A6	PRPS1	P09329	751
COL4A6	PRPS1L1	P21108	750
COL4A6	SMPX	Q9UHP9	667
COL4A6	PRPS2	P11908	586
COL4A6	CNIH1	O95406	557
COL4A6	CNIH3	Q8TBE1	546
COL4A6	IGBP1	P78318	531
COL4A6	AIFM1	O95831	530
COL4A6	MED12	Q93074	491
COL4A6	COL4A5	P29400	478
COL4A6	COL1A1	P02452	466
COL4A6	SEC16B	Q96JE7	461
COL4A6	ITGA5	P08648	454
COL4A6	LAMA4	Q16363	442

IntAct

15 interactions, top by confidence:

A	B	Type	Score
APP	COL4A6	psi-mi:“MI:0915”(physical association)	0.560
FKBP9	CASC3	psi-mi:“MI:0914”(association)	0.530
PLOD3	COL4A1	psi-mi:“MI:0914”(association)	0.530
COL4A6	KLK6	psi-mi:“MI:0570”(protein cleavage)	0.440
COL4A6	NOTCH1	psi-mi:“MI:0915”(physical association)	0.370
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
P4HA1	POLRMT	psi-mi:“MI:0914”(association)	0.350
PLOD1	PLK4	psi-mi:“MI:0914”(association)	0.350
C1QTNF1	PLOD2	psi-mi:“MI:0914”(association)	0.350
LAIR2	PLOD3	psi-mi:“MI:0914”(association)	0.350
COL4A6	OSM	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (20): SUMF1 (Co-fractionation), COL4A6 (Co-localization), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (Two-hybrid), COL4A6 (Two-hybrid), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (Affinity Capture-MS), COL4A6 (PCA)

ESM2 similar proteins: A0A060WQA3, A0MSJ1, A5PN28, A6NHN0, A8WR59, C0HLN2, C7DZK3, O35167, O35348, O76368, O88207, P08122, P08572, P12106, P12107, P12108, P13942, P20849, P20850, P20908, P20909, P25067, P25940, P53420, P83371, P98085, Q01955, Q03637, Q05722, Q07092, Q07643, Q0VF58, Q14031, Q14055, Q14993, Q17RW2, Q28083, Q30D77, Q32S24, Q4ZJM7

Diamond homologs: P02462, P02463, P08120, P08122, P08572, P17139, P17140, P27393, P29400, P53420, P55787, Q01955, Q14031, Q28084, Q28247, Q29442, Q7SIB2, Q7SIB3, Q9QZR9, Q9QZS0

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
COL4A6	“up-regulates activity”	“A2/b1 integrin”	binding
COL4A6	up-regulates	ECM_synthesis
COL4A6	“up-regulates activity”	“A1/b1 integrin”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Collagen biosynthesis and modifying enzymes	5	56.8×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
collagen fibril organization	5	70.2×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

905 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	5
Uncertain significance	326
Likely benign	247
Benign	87

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
102425	NM_033641.4(COL4A6):c.1768G>A (p.Gly590Ser)	Likely pathogenic
191253	NM_033641.4(COL4A6):c.5071T>G (p.Ter1691Glu)	Likely pathogenic
3250380	NM_033641.4(COL4A6):c.511G>C (p.Gly171Arg)	Likely pathogenic
3340154	NM_033641.4(COL4A6):c.2998C>T (p.Pro1000Ser)	Likely pathogenic
4845744	NM_033641.4(COL4A6):c.1188_1195del (p.Gly397fs)	Likely pathogenic

SpliceAI

6747 predictions. Top by Δscore:

Variant	Effect	Δscore
X:108157256:GTGTG:G	acceptor_gain	1.0000
X:108157257:TGTG:T	acceptor_gain	1.0000
X:108160652:CTC:C	acceptor_gain	1.0000
X:108161615:AGACC:A	donor_loss	1.0000
X:108161616:GACCT:G	donor_loss	1.0000
X:108161617:A:AT	donor_loss	1.0000
X:108161618:C:A	donor_loss	1.0000
X:108161732:GAGC:G	acceptor_gain	1.0000
X:108161736:C:CC	acceptor_gain	1.0000
X:108161736:CTGCA:C	acceptor_loss	1.0000
X:108161737:T:A	acceptor_loss	1.0000
X:108162888:TCA:T	donor_loss	1.0000
X:108162889:CACCT:C	donor_loss	1.0000
X:108162890:ACC:A	donor_loss	1.0000
X:108162891:C:A	donor_loss	1.0000
X:108163034:AGAGC:A	acceptor_gain	1.0000
X:108163035:GAGC:G	acceptor_gain	1.0000
X:108163038:CCT:C	acceptor_loss	1.0000
X:108163039:C:CC	acceptor_gain	1.0000
X:108163039:CTGTG:C	acceptor_loss	1.0000
X:108163046:C:CT	acceptor_gain	1.0000
X:108163047:A:T	acceptor_gain	1.0000
X:108163049:G:C	acceptor_gain	1.0000
X:108164873:GTAC:G	donor_loss	1.0000
X:108164874:TA:T	donor_loss	1.0000
X:108164876:CCTT:C	donor_loss	1.0000
X:108164930:C:CA	donor_gain	1.0000
X:108164935:AGGC:A	donor_gain	1.0000
X:108165358:T:TA	donor_gain	1.0000
X:108166747:ATAG:A	donor_gain	1.0000

AlphaMissense

10581 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:108157025:C:G	C1684S	0.999
X:108157026:A:T	C1684S	0.999
X:108157117:C:A	W1653C	0.999
X:108157117:C:G	W1653C	0.999
X:108157119:A:G	W1653R	0.999
X:108157119:A:T	W1653R	0.999
X:108157123:A:C	S1651R	0.999
X:108157123:A:T	S1651R	0.999
X:108157125:T:G	S1651R	0.999
X:108157147:G:C	C1643W	0.999
X:108157149:A:G	C1643R	0.999
X:108157168:G:C	C1636W	0.999
X:108157169:C:G	C1636S	0.999
X:108157170:A:G	C1636R	0.999
X:108157170:A:T	C1636S	0.999
X:108157204:G:C	C1624W	0.999
X:108157205:C:G	C1624S	0.999
X:108157205:C:T	C1624Y	0.999
X:108157206:A:G	C1624R	0.999
X:108157206:A:T	C1624S	0.999
X:108159472:G:A	S1602F	0.999
X:108159573:G:C	C1568W	0.999
X:108159574:C:G	C1568S	0.999
X:108159575:A:T	C1568S	0.999
X:108159579:G:C	S1566R	0.999
X:108159579:G:T	S1566R	0.999
X:108159581:T:G	S1566R	0.999
X:108159643:A:G	L1545P	0.999
X:108159645:C:A	W1544C	0.999
X:108159645:C:G	W1544C	0.999

dbSNP variants (sampled 300 via entrez): RS1000034543 (X:108425113 A>G), RS1000052275 (X:108358086 C>T), RS1000056392 (X:108162571 G>A), RS1000057126 (X:108353026 G>C), RS1000091353 (X:108270579 G>GT), RS1000093278 (X:108232662 C>T), RS1000103739 (X:108432827 C>G), RS1000138249 (X:108166176 C>T), RS1000163745 (X:108364164 G>A), RS1000164283 (X:108328115 A>G), RS1000167195 (X:108195892 A>G), RS1000212604 (X:108421040 G>T), RS1000226689 (X:108287917 T>A), RS1000246039 (X:108270787 T>C), RS1000253538 (X:108399508 A>T)

Disease associations

OMIM: gene MIM:303631 | disease phenotypes: MIM:300914

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, X-linked 6	Strong	X-linked
X-linked nonsyndromic hearing loss	Supportive	X-linked
premature ovarian failure 1	Limited	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hearing loss, X-linked 6	Limited	XL

Mondo (5): hearing loss, X-linked 6 (MONDO:0010484), hearing loss disorder (MONDO:0005365), lymphedema (MONDO:0019297), premature ovarian failure 1 (MONDO:0010706), X-linked nonsyndromic hearing loss (MONDO:0019586)

Orphanet (2): Rare X-linked non-syndromic sensorineural deafness type DFN (Orphanet:90625), OBSOLETE: Lymphedema (Orphanet:79383)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000093	Proteinuria
HP:0000112	Nephropathy
HP:0000407	Sensorineural hearing impairment
HP:0000478	Abnormality of the eye
HP:0000491	Keratitis
HP:0000518	Cataract
HP:0000545	Myopia
HP:0000790	Hematuria
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001824	Weight loss
HP:0002013	Vomiting
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002031	Abnormal esophagus morphology
HP:0002094	Dyspnea
HP:0002205	Recurrent respiratory infections
HP:0002571	Achalasia
HP:0003262	Anti-smooth muscle antibody positivity
HP:0003577	Congenital onset
HP:0003774	Stage 5 chronic kidney disease
HP:0006524	Tracheobronchial leiomyomatosis
HP:0006756	Diffuse leiomyomatosis
HP:0008619	Bilateral sensorineural hearing impairment
HP:0010450	Esophageal stenosis
HP:0010460	Abnormality of the female genitalia
HP:0010614	Fibroma
HP:0010784	Uterine neoplasm
HP:0011373	Incomplete partition of the cochlea
HP:0011501	Anterior lenticonus

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002706_6	Electrodermal activity	2.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008209	Lymphedema	C15.604.496

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364188 (PROTEIN COMPLEX GROUP)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases expression, decreases methylation, affects cotreatment	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation	3
Tobacco Smoke Pollution	decreases expression	3
bisphenol A	increases methylation, affects cotreatment, decreases expression	2
trichostatin A	decreases expression, increases expression	2
methacrylaldehyde	affects cotreatment, affects expression, affects oxidation, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, affects expression, affects oxidation, increases oxidation, increases abundance	2
Dexamethasone	affects cotreatment, decreases expression	2
Doxorubicin	increases expression	2
Nickel	decreases expression	2
Ozone	increases abundance, affects cotreatment, affects expression, affects oxidation, increases oxidation	2
Tretinoin	decreases expression, increases expression	2
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	2
alpha-pinene	affects oxidation, increases abundance, affects cotreatment, affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
afimoxifene	decreases expression	1
sulforaphane	decreases expression	1
boron nitride	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
benzo(k)fluoranthene	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
benz(a)anthracene	decreases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1NZ	Abcam HeLa COL4A6 KO	Cancer cell line	Female
CVCL_D8J7	Ubigene HCT 116 COL4A6 KO	Cancer cell line	Male
CVCL_E0AP	Ubigene HeLa COL4A6 KO	Cancer cell line	Female

Clinical trials (associated diseases)

309 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT00471731	Not specified	COMPLETED	Dry Eye in Women With Turner Syndrome and Women With Premature Ovarian Failure
NCT01023178	Not specified	COMPLETED	Comparison of Transdermal and Oral Estrogens in Adolescent Girls With Ovarian Failure
NCT01177891	Not specified	COMPLETED	Genetic Analysis of Familial Cases of Premature Ovarian Failure
NCT02780791	Not specified	TERMINATED	Maturation of Follicles After Transplantation of Ovarian Tissue Into the Pelvic Wall and the Ovary
NCT05443282	Not specified	COMPLETED	Ovarian Reserve and Matrix Metalloproteinases
NCT07117682	Not specified	NOT_YET_RECRUITING	Safety and Efficacy of Autologous Adipose-Derived Regenerative Cells (ADRCs) Injection for Improving Diminished Ovarian Reserve
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus