COL6A1

Chr 21ADAR

collagen type VI alpha 1 chain

Also known as: BTHLM1, BTHLM1A, OPLL, UCHMD1, UCHMD1A

The protein encodes the alpha-1 subunit of type VI collagen, which forms heterotrimers that are major structural components of extracellular matrix microfibrils. Mutations cause Bethlem myopathy and Ullrich congenital muscular dystrophy through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves disruption of the collagen VI heterotrimer structure, compromising extracellular matrix integrity in muscle and other tissues.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismAD/ARLOEUF 0.232 OMIM phenotypes
Clinical SummaryCOL6A1
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Gene-Disease Validity (ClinGen)
collagen 6-related myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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.
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GeneReview available — COL6A1
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.23LOEUF
pLI 1.000
Z-score 6.45
OE 0.13 (0.070.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
0.50Z-score
OE missense 0.95 (0.891.01)
644 obs / 680.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.13 (0.070.23)
00.351.4
Missense OE0.95 (0.891.01)
00.61.4
Synonymous OE1.10
01.21.6
LoF obs/exp: 8 / 63.5Missense obs/exp: 644 / 680.8Syn Z: -1.42
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCOL6A1-related myopathyOTHERAD
DN
0.5576th %ile
GOF
0.6247th %ile
LOF
0.53top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.23
DN1 literature citation

Literature Evidence

DNThus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers.PMID:12840783
LOFReduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency.PMID:9580662

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

COL6A1 · 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

No active trials found for this gene.

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Clinical Literature
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