COL12A1

Chr 6ARAD

collagen type XII alpha 1 chain

ENSG00000111799UniProt: Q99715

Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix

Primary Disease Associations & Inheritance

?Ullrich congenital muscular dystrophy 2MIM #616470
AR
Bethlem myopathy 2MIM #616471
AD
761
ClinVar variants
28
Pathogenic / LP
0.97
pLI score· haploinsufficient
0
Active trials
Clinical Summary— COL12A1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 446 VUS of 761 total submissions
Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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.
0.28LOEUF
pLI 0.974
Z-score 9.16
OE 0.21 (0.16–0.28)
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.
2.11Z-score
OE missense 0.85 (0.82–0.89)
1423 obs / 1664.8 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.0.21 (0.16–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.82–0.89)
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: 33 / 156.7Missense obs/exp: 1423 / 1664.8Syn Z: -0.34

ClinVar Variant Classifications

761 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic15
VUS446
Likely Benign267
Benign12
Conflicting8
13
Pathogenic
15
Likely Pathogenic
446
VUS
267
Likely Benign
12
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
6
0
13
Likely Pathogenic
14
0
1
0
15
VUS
6
394
37
9
446
Likely Benign
0
17
109
141
267
Benign
0
0
4
8
12
Conflicting
—8
Total27411157158761

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

View in ClinVar →

Protein Context — Lollipop Plot

COL12A1 · 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

?Ullrich congenital muscular dystrophy 2

MIM #616470

Molecular basis of disorder known

Autosomal recessive

Bethlem myopathy 2

MIM #616471

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Myopathic Ehlers-Danlos Syndrome (mEDS) Related to COL12A1: Two Novel Families and Literature Review.
Merlini L et al.·Int J Mol Sci
2025Review
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
Caffeine enhances antitumor T-cell activity by suppressing kynurenine pathway in colorectal cancer.
Liu Y et al.·Nat Commun
2025
COL12A1 as a prognostic biomarker links immunotherapy response in breast cancer.
Yan Y et al.·Endocr Relat Cancer
2023
COL12A1 Gene Variant and a Review of the Literature: A Case Report of Ullrich Congenital Muscular Dystrophy.
İpek R et al.·Mol Syndromol
2024Case report
Epigenetic dysregulation-mediated COL12A1 upregulation predicts worse outcome in intrahepatic cholangiocarcinoma patients.
Tang Z et al.·Clin Epigenetics
2023Cohort
Multiomics analysis of COL12A1 as a promising prognostic biomarker for immune-related treatment of gastric cancer.
Shi J et al.·Discov Oncol
2025
Longitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer.
Li Y et al.·Nat Commun
2024Natural history
COL12A1 rs970547 Polymorphism Does Not Alter Susceptibility to Anterior Cruciate Ligament Rupture: A Meta-Analysis.
Lv ZT et al.·Front Genet
2021
Clinical characterization of Collagen XII-related disease caused by biallelic COL12A1 variants.
McCarty RM et al.·Ann Clin Transl Neurol
2025
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