COL4A6

Chr XXLR

collagen type IV alpha 6 chain

Also known as: CXDELq22.3, DELXq22.3, DFNX6

NCBI Gene: 1288ENSG00000197565UniProt: Q14031

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. [provided by RefSeq, Dec 2013]

Primary Disease Associations & Inheritance

?Deafness, X-linked 6MIM #300914
XLR
510
ClinVar variants
33
Pathogenic / LP
0.90
pLI score
0
Active trials
Clinical Summary— COL4A6
🧬
Gene-Disease Validity (ClinGen)
hearing loss, X-linked 6 · XLLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.90) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 236 VUS of 510 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.32LOEUF
pLI 0.899
Z-score 5.76
OE 0.20 (0.13–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.48Z-score
OE missense 0.84 (0.78–0.90)
538 obs / 643.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.13–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.78–0.90)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 12 / 60.3Missense obs/exp: 538 / 643.8Syn Z: -0.23

ClinVar Variant Classifications

510 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic4
VUS236
Likely Benign171
Benign59
Conflicting11
29
Pathogenic
4
Likely Pathogenic
236
VUS
171
Likely Benign
59
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
29
0
29
Likely Pathogenic
0
3
1
0
4
VUS
3
204
27
2
236
Likely Benign
0
14
80
77
171
Benign
0
3
44
12
59
Conflicting
—11
Total322418191510

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

COL4A6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Deafness, X-linked 6

MIM #300914

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Alport's syndrome.
Bruni V et al.·J Biol Regul Homeost Agents
2019
Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications.
O'Brien A et al.·Eur J Hum Genet
2022Case report
Collagen IV in Gould syndrome and Alport syndrome.
Massoudi D et al.·Nat Rev Nephrol
2025Review
Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation.
Tang S et al.·PLoS One
2021
Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis.
Nozu K et al.·J Hum Genet
2017
Alport syndrome and diffuse leiomyomatosis. Clinical aspects, pathology, molecular biology and extracellular matrix studies. A synthesis.
Garcia-Torres R et al.·Nephrologie
2000Review
Deletion of the 5'exons of COL4A6 is not needed for the development of diffuse leiomyomatosis in patients with Alport syndrome.
Sá MJ et al.·J Med Genet
2013Case report
Genomics of uterine leiomyomas: insights from high-throughput sequencing.
Mehine M et al.·Fertil Steril
2014Review
Clinical and molecular diagnosis of Alport syndrome.
Kashtan CE·Proc Assoc Am Physicians
1995Review
Missense mutations in COL4A5 or COL4A6 genes may cause cerebrovascular fibromuscular dysplasia: Case report and literature review.
Wang X et al.·Medicine (Baltimore)
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools