COL3A1

Chr 2ADAR

collagen type III alpha 1 chain

NCBI Gene: 1281ENSG00000168542UniProt: P02461

Collagen type III occurs in most soft connective tissues along with type I collagen. Involved in regulation of cortical development. Is the major ligand of ADGRG1 in the developing brain and binding to ADGRG1 inhibits neuronal migration and activates the RhoA pathway by coupling ADGRG1 to GNA13 and possibly GNA12

Primary Disease Associations & Inheritance

Ehlers-Danlos syndrome, vascular typeMIM #130050
AD
Polymicrogyria with or without vascular-type EDSMIM #618343
AR
551
ClinVar variants
93
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— COL3A1
🧬
Gene-Disease Validity (ClinGen)
Ehlers-Danlos syndrome, vascular type · ADDefinitive

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
93 Pathogenic / Likely Pathogenic· 213 VUS of 551 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.10LOEUF
pLI 1.000
Z-score 8.59
OE 0.04 (0.02–0.10)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
4.09Z-score
OE missense 0.61 (0.56–0.65)
516 obs / 851.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.04 (0.02–0.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.56–0.65)
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.1.07
0≤1.21.6
LoF obs/exp: 4 / 93.7Missense obs/exp: 516 / 851.7Syn Z: -0.96

ClinVar Variant Classifications

551 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic62
VUS213
Likely Benign238
Benign4
Conflicting3
31
Pathogenic
62
Likely Pathogenic
213
VUS
238
Likely Benign
4
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
4
8
0
31
Likely Pathogenic
9
49
4
0
62
VUS
2
187
22
2
213
Likely Benign
0
1
137
100
238
Benign
0
0
4
0
4
Conflicting
—3
Total30241175102551

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

View in ClinVar →

Protein Context — Lollipop Plot

COL3A1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL3A1-related Ehlers-Danlos syndrome

definitive
ADDominant NegativeAltered Gene Product Structure
Skin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ehlers-Danlos syndrome, vascular type

MIM #130050

Molecular basis of disorder known

Autosomal dominant

Polymicrogyria with or without vascular-type EDS

MIM #618343

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — COL3A1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases.
Kuivaniemi H et al.·Gene
2019Review
Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV).
Pepin MG et al.·Genet Med
2014Functional
Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome.
Byers PH et al.·Am J Med Genet C Semin Med Genet
2017Review
Specifications and validation of the ACMG/AMP criteria for clinical interpretation of sequence variants in collagen genes associated with joint hypermobility.
Leone MP et al.·Hum Genet
2023
Diagnosis and management of vascular Ehlers-Danlos syndrome: Experience of the UK national diagnostic service, Sheffield.
Bowen JM et al.·Eur J Hum Genet
2023Review
Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.
Pepin M et al.·N Engl J Med
2000
Acquired resistance to immunotherapy by physical barriers with cancer cell-expressing collagens in non-small cell lung cancer.
Wang M et al.·Proc Natl Acad Sci U S A
2025
The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.
Frank M et al.·Eur J Hum Genet
2015
A comparative study of the effects of retinol and retinoic acid on histological, molecular, and clinical properties of human skin.
Kong R et al.·J Cosmet Dermatol
2016
Vascular Ehlers-Danlos syndrome.
Germain DP et al.·Ann Genet
2004Review
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
Scarring Alopecia

Non-Ablative Laser to Treat Scarring Alopecia With Hair Follicle Gene Expression Analysis

RECRUITING
NCT06946550Phase NAMontefiore Medical CenterStarted 2025-12-09
1470nm non-ablative fractional laser
Vascular Ehlers-Danlos Syndrome

Heart Coherence Training on Vascular Ehlers-Danlos Syndrome Patients

RECRUITING
NCT05994664Phase NABaylor College of MedicineStarted 2024-04-01
Heartmath InterventionControl Group
Ehlers-Danlos Syndrome, Vascular Type

SEDVasc (RaDiCo Cohort) (RaDiCo-SEDVasc)

ACTIVE NOT RECRUITING
NCT05976841Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2016-12-05
Pelvic Organ ProlapseFemale Urogenital Diseases

Pelvic Organs Prolapse Treatment Using Neodymium Laser

ACTIVE NOT RECRUITING
NCT05000957Phase NAMeLSyTech, LtdStarted 2021-10-03
Laser TreatmentBlood analysisСlinical urine test

External Resources

Links to major genomics databases and tools