COL4A3

Chr 2ADAR

collagen type IV alpha 3 chain

Also known as: ATS2, ATS3, ATS3A, ATS3B, BFH2

NCBI Gene: 1285ENSG00000169031UniProt: Q01955OMIM: 120070

Type IV collagen alpha 3 forms the major structural component of glomerular basement membranes, creating a meshwork with laminins and other proteins. Mutations cause autosomal recessive Alport syndrome, characterized by progressive hereditary nephritis often accompanied by sensorineural hearing loss and ocular abnormalities. The gene is not constrained against loss-of-function variants, consistent with the recessive inheritance pattern where both copies must be affected to cause disease.

GeneReviewsOMIMResearchSummary from RefSeq, UniProt
LOFmechanismAD/ARLOEUF 0.523 OMIM phenotypes
Clinical Summary— COL4A3
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Gene-Disease Validity (ClinGen)
Alport syndrome · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
110 unique Pathogenic / Likely Pathogenic· 52 VUS of 200 total submissions
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Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — COL4A3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
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
1.99Z-score
OE missense 0.82 (0.77–0.87)
763 obs / 934.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.40 (0.31–0.52)
0≤0.351.4
Missense OE0.82 (0.77–0.87)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 38 / 95.4Missense obs/exp: 763 / 934.6Syn Z: 0.54
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCOL4A3-related Alport syndrome (monoallelic)LOFAD
definitiveCOL4A3-related Alport syndrome (biallelic)LOFAR
DN
0.77top 25%
GOF
0.5758th %ile
LOF
0.3454th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe mutations of heterozygous patients are likely dominant, since no change was identified in the second allele even by sequencing, and they are predicted to result in shortened or abnormal chains with a possible dominant-negative effect.PMID:12028435

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic104
VUS52
Likely Benign5
Benign1
Conflicting2
6
Pathogenic
104
Likely Pathogenic
52
VUS
5
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
1
1
0
6
Likely Pathogenic
22
80
2
0
104
VUS
0
47
4
1
52
Likely Benign
0
1
2
2
5
Benign
0
0
1
0
1
Conflicting
—2
Total26129103170

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.

3D Protein StructureAlphaFold

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)

ACTIVE NOT 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

RECRUITING
NCT07211685Phase PHASE2BayerStarted 2025-11-19
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
Alport Syndrome, X-LinkedAlport Syndrome, Autosomal Recessive

EXACT Study: A Blinded Study in Patients With Alport Syndrome to Evaluate Exaluren Efficacy and Safety

NOT YET RECRUITING
NCT07523581Phase PHASE2Eloxx Pharmaceuticals, Inc.Started 2026-05-30
Exaluren
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
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
Alport Syndrome.
Chavez E et al.·Adv Kidney Dis Health
2024Review
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
Alport syndrome and Alport kidney diseases - elucidating the disease spectrum.
Puapatanakul P et al.·Curr Opin Nephrol Hypertens
2024Review
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Phenotype of autosomal dominant Alport syndrome with a likely pathogenic heterozygous variant in the COL4A3 gene (Gly366Arg) and incidental teratozoospermia: A case report.
Martín Moreno V et al.·An Sist Sanit Navar
2026Case report
Clinical Insights Into the COL4A3 p.Gly407Arg Variant in Alport Syndrome.
Gomes AM et al.·Kidney360
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
2026Open 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
2025Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients