COL4A5

Chr XXLD

collagen type IV alpha 5 chain

NCBI Gene: 1287ENSG00000188153UniProt: P29400

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

Primary Disease Associations & Inheritance

Alport syndrome 1, X-linkedMIM #301050
XLD
420
ClinVar variants
201
Pathogenic / LP
1.00
pLI score· haploinsufficient
6
Active trials
Clinical Summary— COL4A5
🧬
Gene-Disease Validity (ClinGen)
Alport syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
201 Pathogenic / Likely Pathogenic· 176 VUS of 420 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available

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.
0.19LOEUF
pLI 1.000
Z-score 6.59
OE 0.10 (0.05–0.19)
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.
2.50Z-score
OE missense 0.72 (0.67–0.78)
474 obs / 653.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.10 (0.05–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.67–0.78)
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.1.03
0≤1.21.6
LoF obs/exp: 6 / 61.9Missense obs/exp: 474 / 653.9Syn Z: -0.36

ClinVar Variant Classifications

420 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic133
VUS176
Likely Benign37
Benign1
Conflicting5
68
Pathogenic
133
Likely Pathogenic
176
VUS
37
Likely Benign
1
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
28
18
0
68
Likely Pathogenic
41
77
15
0
133
VUS
0
130
39
7
176
Likely Benign
0
4
19
14
37
Benign
0
0
1
0
1
Conflicting
—5
Total632399221420

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

View in ClinVar →

Protein Context — Lollipop Plot

COL4A5 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL4A5-related Alport syndrome

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
EyeSkinEar
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Alport syndrome 1, X-linked

MIM #301050

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — COL4A5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Guidelines for Genetic Testing and Management of Alport Syndrome.
Savige J et al.·Clin J Am Soc Nephrol
2022
Digenic Alport Syndrome.
Savige J et al.·Clin J Am Soc Nephrol
2022Review
Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.
Domingo-Gallego A et al.·Nephrol Dial Transplant
2022
Prevalence Estimates of Predicted Pathogenic COL4A3-COL4A5 Variants in a Population Sequencing Database and Their Implications for Alport Syndrome.
Gibson J et al.·J Am Soc Nephrol
2021
Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel.
Bleyer AJ et al.·Am J Nephrol
2022
Alport syndrome and Alport kidney diseases - elucidating the disease spectrum.
Puapatanakul P et al.·Curr Opin Nephrol Hypertens
2024Review
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
Savige J et al.·PLoS One
2016
Genetic Variants of the COL4A3 , COL4A4 , and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients.
Yuan X et al.·J Am Soc Nephrol
2023Cohort
The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.
De Silva SR et al.·Prog Retin Eye Res
2021Review
Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study.
Furlano M et al.·Am J Kidney Dis
2021Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Hereditary Myopathy With Early Respiratory Failure Associated With an Incidental COL4A5 Variant: A Case Report.
Abu Nahla U et al.·Case Rep Genet
2026🔓 Open AccessCase report
Minnelide ameliorates Col4a5+/- mice by upregulating Col4a5 and alleviating endoplasmic reticulum stress.
Ji BW et al.·Front Pharmacol
2026🔓 Open Access
Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants.
Zhang X et al.·BMC Nephrol
2026🔓 Open Access
Whole-genome sequencing identified a deep intronic COL4A5 variant causing aberrant splicing in a female patient with X-linked Alport syndrome.
Nagano C et al.·CEN Case Rep
2026
Temporal Transcriptomics Leads From Discovery to in Vivo Validation: COL4A3/COL4A6/ COL4A5 and ITGA8 as Novel Arthrofibrosis Biomarkers in Post-traumatic Joint Contracture.
Wang Y et al.·Dose Response
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Alport SyndromeThin Basement Membrane DiseaseAlport Nephropathy

Albuminuria Lowering Effect of Dapagliflozin, Spironolactone and Their Combination in Adult Patients with Alport Syndrome (COMBINE-ALPORT)

RECRUITING
NCT06499948Phase PHASE4Stefan LujinschiStarted 2024-02-26
Treatment with Spironolactone followed by Dapagliflozin followed by their combinationTreatment with Dapagliflozin followed by Spironolactone followed by their combination
Adenine Phosphoribosyltransferase DeficiencyAH AmyloidosisAHL Amyloidosis

National Registry of Rare Kidney Diseases

RECRUITING
NCT06065852UK Kidney AssociationStarted 2009-11-06
Alport Syndrome

Eurbio-Alport (RaDiCo Cohort) (RaDiCo Eurbio-Alport)

RECRUITING
NCT05927467Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2017-05-09
Alport Syndrome

Safety and Efficacy of ACEI in Alport Syndrome Patients With COL4A3/COL4A4/COL4A5 Variants

NOT YET RECRUITING
NCT05133050Phase NAXinhua Hospital, Shanghai Jiao Tong University School of MedicineStarted 2022-01-01
Ramipril
Alport Syndrome

BAY3401016; Biomarker Study Alport

NOT YET RECRUITING
NCT07211685Phase PHASE2BayerStarted 2025-12-02
BAY 3401016Placebo
Alport Syndrome

Genotype-Phenotype Correlations in Patients With Alport Syndrome

RECRUITING
NCT04947813Xinhua Hospital, Shanghai Jiao Tong University School of MedicineStarted 2021-01-01

External Resources

Links to major genomics databases and tools