COL12A1

protein-coding

collagen type XII alpha 1 chain, the group of Fibronectin type III domain containing|Collagen proteoglycans|Collagens

Gene summary

This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Previous symbols:

COL12A1L

MANE transcript

NM_004370.6

Inheritance

AR, AD

ClinVar variants

P:155U:1945B:1156

Top phenotype

Bethlem myopathy 2; Ullrich congenital muscular dystrophy 2

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr6:75,084,326-75,206,267

External References & Databases

Ensembl (ENSG00000111799)

Transcript & Mutation Effects

hg38 • Region Span ~121.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ullrich congenital muscular dystrophy 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014654

Submitter: Labcorp Genetics (formerly Invitae)

Bethlem myopathy 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014655

Submitter: Illumina

Bethlem myopathy 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014655

Submitter: Ambry Genetics

Bethlem myopathy 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0034022

Submitter: Labcorp Genetics (formerly Invitae)

Bethlem myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008029

Submitter: Orphanet

Ullrich congenital muscular dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000355

Submitter: Orphanet

Bethlem myopathy 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0034022

Submitter: Orphanet

Ullrich congenital muscular dystrophy 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014654

Submitter: LiferaOmics

Genetic evidence – Published: PMID: 24334604 Family 1: Two affected siblings from a consanguineous family with homozygous predicted loss-of-function COL12A1 variant Proband (AR predicted null) = 1.0 (1.5 − 0.5 for homozygosity/consanguinity) Individual 2 (affected sibling; segregation) = 0.5 Family 1 total = 1.5; case-control = 0 PMID: 37458870 Family 2: One proband with biallelic missense (non-LoF) COL12A1 variants Proband (AR two non-null variants) = 0.1 Family 2 total = 0.1; segregation = 0; case-control = 0 PMID: 38438125 Family 3: One proband homozygous for a predicted loss-of-function COL12A1 variant Proband (AR predicted null) = 1.5 Family 3 total = 1.5; segregation = 0; case-control = 0 PMID: 34930662 Family 4: One proband compound heterozygous for predicted loss-of-function and missense COL12A1 variants Proband (AR with ≥1 predicted null allele) = 1.5 Family 4 total = 1.5; segregation = 0; case-control = 0 PMID: 39129837 Family 5: One proband homozygous for missense COL12A1 variant; consanguineous family Proband (AR two non-null variants default 0.1) = 0.1 Family 5 total = 0.1; segregation = 0; case-control = 0 Published genetic evidence total = 4.7 / 12 Genetic evidence – Our cases: Family 1: Two affected siblings homozygous for NM_004370.5:c.2911delT; p.(Tyr971ThrfsTer17) (frameshift, predicted null) Proband (AR predicted null) = 1.5 Individual 2 (affected sibling; segregation) = 0.5 Family 1 total = 2.0; segregation = 0.5; case-control = 0 Family 2: One proband homozygous for NM_004370.6:c.756dup; p.(Ser253fs) (frameshift, predicted null); Proband (AR predicted null) = 1.5 Family 2 total = 1.5; segregation = 0; case-control = 0 Our cases contribution = 3.5 / 12 Total genetic evidence (published + our cases) 4.7 + 3.5 = 8.2 / 12 Experimental evidence – Published: PMID: 24334604 Model organism (Col12a1 deficiency recapitulating muscle/connective tissue phenotype) = 2.0 Functional alteration in patient tissue (collagen XII deficiency/dysfunction) = 1.0 Expression = 1.0 Experimental evidence total = 4.0 / 6 Overall score (with our cases) Genetic evidence = 8.2 Experimental evidence = 4.0 Total score = 12.2 Replication over time demonstrated (2014–2024 publications)

Bethlem myopathy 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014655

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Bethlem myopathy 2; Ullrich congenital muscular dystrophy 2AD/AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24334604; 24334769

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL12A1 variants in ClinVar

22 Conditions Cataloged

Bethlem myopathy 2Total: 3426

Ullrich congenital muscular dystrophy 2Total: 3396

not providedTotal: 1091

not specifiedTotal: 519

Inborn genetic diseasesTotal: 398

COL12A1-related disorderTotal: 153

Ullrich congenital muscular dystrophyTotal: 7

COL12A1-related disordersTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004370.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			31 clinvar	769 clinvar	32 clinvar	832
missense	2 clinvar	15 clinvar	1862 clinvar	346 clinvar	5 clinvar	2230
nonsense	19 clinvar	20 clinvar	13 clinvar	2 clinvar		54
start loss			1 clinvar			1
frameshift	28 clinvar	23 clinvar	14 clinvar			65
splice donor/acceptor (+/-2bp)	8 clinvar	40 clinvar	24 clinvar	2 clinvar		74
Total	57	98	1945	1119	37	3256

Highest pathogenic variant AF is 0.000017970277

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004370.6	RefSeq	NP_004361.3	65	MANE Select
ENST00000322507.13	Ensembl	ENSP00000325146.8	65	MANE Select
NM_001424113.1	RefSeq	NP_001411042.1	65	Standard
NM_001424114.1	RefSeq	NP_001411043.1	64	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Collagen chain trimerization
Collagen biosynthesis and modifying enzymes
Collagen degradation
Collagen formation

Biological Process

skeletal system development
growth plate cartilage chondrocyte morphogenesis
cell adhesion
collagen fibril organization
endodermal cell differentiation

Molecular Function

extracellular matrix structural constituent conferring tensile strength

Cellular Component

extracellular region
collagen type XII trimer
extracellular space
endoplasmic reticulum lumen
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322507
Coding exons: 65
Length: 121726
Individuals with no LoFs: 124752
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 124804
p: 0.000208

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.11	1423	1.66e+3	0.855	0.0000889	19725
Missense (PolyPhen)		656	850.06	0.77171		10050
Synonymous	-0.336	609	599	1.02	0.0000334	6190
Loss of Function	9.16	33	157	0.211	0.00000858	1944

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00019	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00050	0.00050	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00037	0.00036	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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. {ECO:0000250}.;
Disease: DISEASE: Ullrich congenital muscular dystrophy 2 (UCMD2) [MIM:616470]: A form of Ullrich muscular dystrophy, a congenital myopathy characterized by muscle weakness and multiple joint contractures, generally noted at birth or early infancy. The clinical course is more severe than in Bethlem myopathy. {ECO:0000269|PubMed:24334604}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bethlem myopathy 2 (BTHLM2) [MIM:616471]: A form of Bethlem myopathy, a benign proximal myopathy characterized by early childhood onset and joint contractures most frequently affecting the elbows and ankles. BTHLM2 inheritance is autosomal dominant. {ECO:0000269|PubMed:24334604, ECO:0000269|PubMed:24334769}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.144

Intolerance Scores

LoFtool: 0.0488
RVIS EVS: -1.63
RVIS percentile EVS: 2.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.602

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium