COL4A3

Chr 2ADAR

collagen type IV alpha 3 chain

NCBI Gene: 1285ENSG00000169031UniProt: Q01955

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 3A, autosomal dominantMIM #104200
AD
Alport syndrome 3B, autosomal recessiveMIM #620536
AR
Hematuria, benign familial, 2MIM #620320
AD
570
ClinVar variants
155
Pathogenic / LP
0.00
pLI score
5
Active trials
Clinical Summary— COL4A3
🧬
Gene-Disease Validity (ClinGen)
Alport syndrome · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
155 Pathogenic / Likely Pathogenic· 314 VUS of 570 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.52LOEUF
pLI 0.000
Z-score 5.45
OE 0.40 (0.31–0.52)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.99Z-score
OE missense 0.82 (0.77–0.87)
763 obs / 934.6 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.0.40 (0.31–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.77–0.87)
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.0.96
0≤1.21.6
LoF obs/exp: 38 / 95.4Missense obs/exp: 763 / 934.6Syn Z: 0.54

ClinVar Variant Classifications

570 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic130
VUS314
Likely Benign84
Benign2
Conflicting15
25
Pathogenic
130
Likely Pathogenic
314
VUS
84
Likely Benign
2
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
5
5
0
25
Likely Pathogenic
47
75
8
0
130
VUS
3
244
50
17
314
Likely Benign
0
6
49
29
84
Benign
0
1
0
1
2
Conflicting
—15
Total6533111247570

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

View in ClinVar →

Protein Context — Lollipop Plot

COL4A3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL4A3-related Alport syndrome (monoallelic)

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkinEar
G2P ↗

COL4A3-related Alport syndrome (biallelic)

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkinEar
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Alport syndrome 3A, autosomal dominant

MIM #104200

Molecular basis of disorder known

Autosomal dominant

Alport syndrome 3B, autosomal recessive

MIM #620536

Molecular basis of disorder known

Autosomal recessive

Hematuria, benign familial, 2

MIM #620320

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — COL4A3
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
Alport Syndrome.
Chavez E et al.·Adv Kidney Dis Health
2024Review
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
Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome.
Zhang Y et al.·Pediatr Nephrol
2021Cohort
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
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
Savige J et al.·PLoS One
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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
From screening to strategy: Clinical implications of COL4A3/COL4A4 variants found in reproductive genetic testing.
Butler G et al.·Eur J Hum Genet
2026
Age at disease onset and risk of chronic kidney disease in patients with heterozygous disease-causing variants in COL4A3 and COL4A4.
Hu N et al.·Clin Kidney J
2025🔓 Open AccessCohort
Pathogenic synonymous variation of the COL4A3 gene causing Alport syndrome comorbid with IgA deposition in a toddler: a case report.
Shao P et al.·BMC Nephrol
2025🔓 Open AccessCase report
Novel COL4A3-COL4A5 variants and digenic inheritance in pediatric Alport syndrome from Southwestern China.
Chen JY et al.·Sci Rep
2025🔓 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
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
Keratoconus

The Collagen Factors of Rapid Progression of Keratoconus in Children.

RECRUITING
NCT06722937Zhongshan Ophthalmic Center, Sun Yat-sen UniversityStarted 2023-04-14
Observation
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