hearing loss, X-linked 6

Summary

hearing loss, X-linked 6 (MONDO:0010484) is a disease caused by COL4A6 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: COL4A6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 65

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hearing loss, X-linked 6
Mondo ID	MONDO:0010484
OMIM	300914
DOID	DOID:0111740
UMLS	C3806737
MedGen	813067
GARD	0018097
Is cancer (heuristic)	no

Also known as: COL4A6 X-linked nonsyndromic deafness · deafness, X-linked 6 · deafness, X-linked 6, X-linked recessive · deafness, X-linked type 6 · DFNX6 · hearing loss, X-linked 6 · X-linked nonsyndromic deafness caused by mutation in COL4A6

Data availability: 65 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › auditory system disorder › hearing disorder › hearing loss disorder › nonsyndromic genetic hearing loss › X-linked nonsyndromic hearing loss › hearing loss, X-linked 6

Related subtypes (5): hearing loss, X-linked 3, hearing loss, X-linked 4, X-linked hereditary sensory and autonomic neuropathy with hearing loss, X-linked mixed hearing loss with perilymphatic gusher, hearing loss, X-linked 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

65 retrieved; paginated sample, class counts are floors:

33 benign, 15 benign/likely benign, 8 uncertain significance, 5 likely pathogenic, 3 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3358929	NM_033641.4(COL4A6):c.[1384G>A;2230G>A]		Likely pathogenic	criteria provided, single submitter
102425	NM_033641.4(COL4A6):c.1768G>A (p.Gly590Ser)	COL4A6	Likely pathogenic	criteria provided, single submitter
3250380	NM_033641.4(COL4A6):c.511G>C (p.Gly171Arg)	COL4A6	Likely pathogenic	criteria provided, single submitter
3340154	NM_033641.4(COL4A6):c.2998C>T (p.Pro1000Ser)	COL4A6	Likely pathogenic	no assertion criteria provided
4845744	NM_033641.4(COL4A6):c.1188_1195del (p.Gly397fs)	COL4A6	Likely pathogenic	criteria provided, single submitter
2351887	NM_033641.4(COL4A6):c.2230G>A (p.Gly744Ser)	COL4A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
772297	NM_033641.4(COL4A6):c.1886G>A (p.Arg629His)	COL4A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
982952	NM_033641.4(COL4A6):c.4642G>A (p.Ala1548Thr)	COL4A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699298	NM_033641.4(COL4A6):c.4768C>T (p.Pro1590Ser)	COL4A6	Uncertain significance	criteria provided, single submitter
2440325	NM_033641.4(COL4A6):c.74C>T (p.Ser25Phe)	COL4A6	Uncertain significance	criteria provided, single submitter
2440326	NM_033641.4(COL4A6):c.2506G>A (p.Gly836Ser)	COL4A6	Uncertain significance	criteria provided, single submitter
2440327	NM_033641.4(COL4A6):c.628G>C (p.Gly210Arg)	COL4A6	Uncertain significance	criteria provided, single submitter
2512804	NM_033641.4(COL4A6):c.4450G>A (p.Gly1484Arg)	COL4A6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3024171	NM_033641.4(COL4A6):c.227G>A (p.Gly76Glu)	COL4A6	Uncertain significance	criteria provided, single submitter
3065545	NM_033641.4(COL4A6):c.546+1G>A	COL4A6	Uncertain significance	criteria provided, single submitter
4056303	NM_033641.4(COL4A6):c.3832C>T (p.Pro1278Ser)	COL4A6	Uncertain significance	criteria provided, single submitter
1235575	NM_033641.4(COL4A6):c.835-6A>G	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1237218	NM_033641.4(COL4A6):c.2409G>A (p.Gly803=)	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1240869	NM_033641.4(COL4A6):c.3809-14G>A	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1255397	NM_033641.4(COL4A6):c.2956+39G>A	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1255399	NM_033641.4(COL4A6):c.949-31C>G	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1255400	NM_033641.4(COL4A6):c.687+30C>A	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1259208	NM_033641.4(COL4A6):c.114C>T (p.Ser38=)	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1265907	NM_033641.4(COL4A6):c.4404G>A (p.Thr1468=)	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1278580	NM_033641.4(COL4A6):c.1922C>T (p.Pro641Leu)	COL4A6	Benign	criteria provided, multiple submitters, no conflicts
1301627	NM_033641.4(COL4A6):c.1952-2785_1952-2784insAGA	COL4A6	Benign	criteria provided, single submitter
1316585	NM_033641.4(COL4A6):c.1533A>G (p.Lys511=)	COL4A6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1318400	NM_033641.4(COL4A6):c.4070-17C>T	COL4A6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1328649	NM_033641.4(COL4A6):c.3138+17C>T	COL4A6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1579443	NM_033641.4(COL4A6):c.2013C>T (p.Pro671=)	COL4A6	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
COL4A6	Strong	X-linked	hearing loss, X-linked 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL4A6	Orphanet:1018	X-linked Alport syndrome-diffuse leiomyomatosis
COL4A6	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL4A6	HGNC:2208	ENSG00000197565	Q14031	Collagen alpha-6(IV) chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL4A6	Collagen alpha-6(IV) chain	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL4A6	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus	1
lower esophagus muscularis layer	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL4A6	197	broad	marker	mucosa of stomach, lower esophagus muscularis layer, lower esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A6	1,535

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL4A6	Q14031	48.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring fibril formation	1	761.3×	0.006	COL4A6
Fibronectin matrix formation	1	571.0×	0.006	COL4A6
Crosslinking of collagen fibrils	1	571.0×	0.006	COL4A6
Attachment of bacteria to epithelial cells	1	496.5×	0.006	COL4A6
Attenuation phase	1	407.9×	0.006	COL4A6
Laminin interactions	1	380.7×	0.006	COL4A6
HSF1 activation	1	380.7×	0.006	COL4A6
HSF1-dependent transactivation	1	317.2×	0.006	COL4A6
Collagen chain trimerization	1	259.6×	0.007	COL4A6
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.007	COL4A6
Collagen degradation	1	175.7×	0.007	COL4A6
Collagen biosynthesis and modifying enzymes	1	170.4×	0.007	COL4A6
Non-integrin membrane-ECM interactions	1	154.3×	0.007	COL4A6
ECM proteoglycans	1	150.3×	0.007	COL4A6
Regulation of HSF1-mediated heat shock response	1	139.3×	0.007	COL4A6
Integrin cell surface interactions	1	134.3×	0.007	COL4A6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen-activated tyrosine kinase receptor signaling pathway	1	1296.3×	0.003	COL4A6
cellular response to amino acid stimulus	1	306.4×	0.006	COL4A6
collagen fibril organization	1	224.7×	0.006	COL4A6
cell adhesion	1	37.5×	0.027	COL4A6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL4A6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	COL4A6

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL4A6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.