COL12A1

Summary

COL12A1 (collagen type XII alpha 1 chain, HGNC:2188) is a protein-coding gene on chromosome 6q13-q14.1, encoding Collagen alpha-1(XII) chain (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.

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.

Source: NCBI Gene 1303 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bethlem myopathy 2 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 4,077 total — 64 pathogenic, 65 likely-pathogenic
• Phenotypes (HPO): 109
• MANE Select transcript: NM_004370

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2188
Approved symbol	COL12A1
Name	collagen type XII alpha 1 chain
Location	6q13-q14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111799
Ensembl biotype	protein_coding
OMIM	120320
Entrez	1303

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000322507, ENST00000345356, ENST00000416123, ENST00000419671, ENST00000425443, ENST00000474564, ENST00000483888, ENST00000486533, ENST00000493109, ENST00000511023, ENST00000680102, ENST00000680981, ENST00000681086, ENST00000898574

RefSeq mRNA: 6 — MANE Select: NM_004370 NM_001424113, NM_001424114, NM_001424115, NM_001424116, NM_004370, NM_080645

CCDS: CCDS43481, CCDS43482

Canonical transcript exons

ENST00000322507 — 66 exons

Exon	Start	End
ENSE00001143728	75087577	75087747
ENSE00001451910	75084326	75086557
ENSE00002020568	75102597	75102692
ENSE00002027630	75205777	75206053
ENSE00002035083	75101999	75102052
ENSE00002042128	75105206	75105292
ENSE00002060425	75109018	75109167
ENSE00002061131	75103757	75103810
ENSE00002069478	75113204	75113313
ENSE00002072250	75113602	75113744
ENSE00002078709	75089106	75089174
ENSE00002087838	75106419	75106496
ENSE00002223671	75134726	75134855
ENSE00002225380	75189552	75189815
ENSE00002226165	75202720	75202827
ENSE00002226533	75138320	75138340
ENSE00002231402	75125127	75125273
ENSE00002233336	75191701	75191760
ENSE00002238930	75146102	75146244
ENSE00002239517	75126351	75126470
ENSE00002240395	75143252	75143388
ENSE00002241339	75116019	75116057
ENSE00002242090	75151141	75151287
ENSE00002243507	75192212	75192355
ENSE00002244571	75142032	75142161
ENSE00002251843	75131940	75132082
ENSE00002254569	75188362	75188535
ENSE00002254999	75189217	75189381
ENSE00002259472	75123948	75124094
ENSE00002260934	75137437	75137579
ENSE00002263833	75194831	75194947
ENSE00002265158	75121302	75121441
ENSE00002268745	75155662	75155854
ENSE00002269885	75177663	75177935
ENSE00002271218	75119350	75119473
ENSE00002274351	75128296	75128425
ENSE00002276950	75165507	75165779
ENSE00002277134	75175038	75175310
ENSE00002280579	75133858	75133997
ENSE00002283546	75133293	75133422
ENSE00002284942	75117382	75117546
ENSE00002284983	75147675	75147804
ENSE00002290023	75152131	75152250
ENSE00002290563	75130091	75130233
ENSE00002293407	75115784	75115922
ENSE00002295676	75123330	75123404
ENSE00002297054	75151867	75152031
ENSE00002299708	75124255	75124371
ENSE00002302170	75148358	75148497
ENSE00002307561	75156257	75156523
ENSE00002308653	75138448	75138580
ENSE00002312585	75152333	75152482
ENSE00002319462	75154416	75154537
ENSE00002320601	75119043	75119186
ENSE00002321341	75138822	75138961
ENSE00002323685	75130852	75130981
ENSE00003510943	75180939	75181211
ENSE00003511699	75091490	75091525
ENSE00003528479	75090110	75090298
ENSE00003538754	75095108	75095179
ENSE00003571150	75183854	75184144
ENSE00003623045	75091323	75091389
ENSE00003630690	75145326	75145455
ENSE00003634763	75183050	75183652
ENSE00003650847	75097253	75097306
ENSE00003683475	75101600	75101653

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 198.4741 / max 10016.9337, expressed in 1349 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74454	166.7181	1267
74453	13.4066	1057
204071	3.1217	708
204070	2.8235	761
204075	1.7505	608
204068	1.6735	604
204061	1.5061	353
74404	1.4462	461
74449	1.0725	358
204066	1.0199	545

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.81	gold quality
calcaneal tendon	UBERON:0003701	99.79	gold quality
cartilage tissue	UBERON:0002418	99.62	gold quality
stromal cell of endometrium	CL:0002255	99.08	gold quality
upper arm skin	UBERON:0004263	99.08	gold quality
pericardium	UBERON:0002407	98.73	gold quality
synovial joint	UBERON:0002217	98.30	gold quality
tendon	UBERON:0000043	98.25	gold quality
mammalian vulva	UBERON:0000997	97.91	gold quality
cauda epididymis	UBERON:0004360	97.80	gold quality
layer of synovial tissue	UBERON:0007616	97.79	gold quality
saphenous vein	UBERON:0007318	97.74	gold quality
right ovary	UBERON:0002118	97.57	gold quality
skin of hip	UBERON:0001554	97.42	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.39	gold quality
left ovary	UBERON:0002119	97.35	gold quality
lower esophagus	UBERON:0013473	97.35	gold quality
myometrium	UBERON:0001296	97.26	gold quality
visceral pleura	UBERON:0002401	97.07	gold quality
smooth muscle tissue	UBERON:0001135	96.95	gold quality
colonic epithelium	UBERON:0000397	96.89	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.82	gold quality
tendon of biceps brachii	UBERON:0008188	96.64	gold quality
body of uterus	UBERON:0009853	96.54	gold quality
tibial nerve	UBERON:0001323	96.53	gold quality
seminal vesicle	UBERON:0000998	96.33	gold quality
endocervix	UBERON:0000458	96.31	gold quality
vena cava	UBERON:0004087	96.17	gold quality
adipose tissue	UBERON:0001013	95.86	gold quality
urethra	UBERON:0000057	95.78	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-10596	yes	2391.10
E-CURD-112	yes	1586.49
E-MTAB-7407	yes	685.28
E-HCAD-10	yes	42.87
E-MTAB-8410	yes	41.41
E-ANND-3	yes	40.64
E-CURD-46	yes	19.66
E-MTAB-9543	yes	16.15
E-CURD-119	yes	12.83
E-MTAB-10042	yes	8.09
E-ENAD-27	yes	6.08
E-MTAB-10290	no	1033.16
E-GEOD-124858	no	532.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

150 targeting COL12A1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-126-5P	100.00	72.71	3180
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AN	99.97	70.91	2817

Literature-anchored findings (GeneRIF, showing 29)

• induction of expression by sheare stress is associated with atherogenesis (PMID:12890494)
• Results suggest that collagens XII and XIV might serve different functions during human embryonic development although their structures are highly similar. (PMID:15609093)
• both COL12A1 and COL4A5 constitute good candidate target genes in the pathogenesis of subungual exostosis (PMID:16284948)
• COL12A1 is associated with anterior cruciate ligament ruptures among females (PMID:19443461)
• this study identifies COL12A1 as the likely gene candidate within the recurrent 6q13 breakpoint and provides an alternative approach for detecting 6q13 anomalies in nondividing cells of chondromyxoid fibroma. (PMID:19648885)
• In addition to binding collagen I, COMP binds to collagens XII and XIV via their C-terminal collagenous domains. (PMID:22573329)
• Type XII collagen is overexpressed in permanent human and mouse corneal scars and could represent a new target to treat corneal scarring. (PMID:22969073)
• COL3A1 rs1800255, COL6A1 rs35796750 and COL12A1 rs970547 were not significantly associated with sit-and-reach, straight leg raise or total shoulder rotation range of motion (PMID:23013106)
• results show that this gene interacts collagen x1 encoded genes to modulate the risk for AT (PMID:23624467)
• collagen alpha-1 (XII) chain was expressed at dramatically higher (~10-fold) levels in breast (PMID:24262153)
• The study indicates that the spectrum of causative genes in extracellular matrix-related myopathies be extended to include COL12A1. (PMID:24334769)
• Extracellular matrix proteins expression profiling in chemoresistant variants of the A2780 ovarian cancer cell line. (PMID:24804215)
• In conclusion, the novel main finding of this study was a significant interaction between the COL5A1 rs12722 T/C and COL12A1 rs970547 A/G variants and risk of anterior cruciate ligament injury. (PMID:25073002)
• Certain core genes, including COL12A1, glutathione Stransferase alpha3 (GSTA3), fibrinogen alpha chain (FGA) and fibrinogen gamma chain (FGG), were the first reported to be associated with Gastric Cancer. Survival analysis suggested that these four genes, COL12A1 (P=0.002), GSTA3 (P=3.4x106), FGA (P=0.00075) and FGG (P=1.4x105), were significant poor prognostic factors of gastric cancer. (PMID:30106150)
• Results identified four pathogenic heterozygous in-frame exon skipping defects in COL12A1 and, one heterozygous arginine-to-cysteine substitution of unclear significance (p.(Arg1863Cys)) in patients with a mixed myopathy/Ehlers-Danlos syndrome spectrum. Variant-specific intracellular accumulation of collagen XII chains, and extracellular decrease of decorin and tenascin-X were observed for the COL12A1 variants. (PMID:31273343)
• COL12A1 is identified as the critical gene on promoting gastric cancer (GC) migration. A reciprocal positive regulation is found between IDO1 and COL12A1 to promote tumor metastasis, mediated by IDO1 metabolite kynurenine and integrin beta1. (PMID:31315643)
• The results highlighted the importance of COL12A1 in gastric cancer (GC) and suggested its potential role as a candidate for clinical outcome prediction and targeted therapy in patients with GC. (PMID:31432110)
• Dominant collagen XII mutations cause a distal myopathy. (PMID:31509352)
• Correlations Between the Genetic Variations in the COL1A1, COL5A1, COL12A1, and beta-fibrinogen Genes and Anterior Cruciate Ligament Injury in Chinese Patients(a). (PMID:32239963)
• Integrated bioinformatics analysis of expression and gene regulation network of COL12A1 in colorectal cancer. (PMID:32356618)
• Role of collagen XII in skin homeostasis and repair. (PMID:32890632)
• Collagen XII mediated cellular and extracellular mechanisms regulate establishment of tendon structure and function. (PMID:33096204)
• A novel mutation in the COL12A1 gene. (PMID:33129849)
• COL12A1 Single Nucleotide Polymorphisms rs240736 and rs970547 Are Not Associated with Temporomandibular Joint Disc Displacement without Reduction. (PMID:34062975)
• Bioinformatics analysis identified MMP14 and COL12A1 as immune-related biomarkers associated with pancreatic adenocarcinoma prognosis. (PMID:34517516)
• Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis. (PMID:35933466)
• Epigenetic dysregulation-mediated COL12A1 upregulation predicts worse outcome in intrahepatic cholangiocarcinoma patients. (PMID:36694230)
• Whole exome sequencing identifies a novel variant in the COL12A1 gene in a family with Ullrich congenital muscular dystrophy 2. (PMID:37458870)
• PABPC1 promotes cell proliferation and metastasis in pancreatic adenocarcinoma by regulating COL12A1 expression. (PMID:37506150)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	col12a1b	ENSDARG00000019601
danio_rerio	col12a1a	ENSDARG00000078322
mus_musculus	Col12a1	ENSMUSG00000032332
rattus_norvegicus	Col12a1	ENSRNOG00000058470

Paralogs (12): COCH (ENSG00000100473), MATN4 (ENSG00000124159), MATN3 (ENSG00000132031), MATN2 (ENSG00000132561), MATN1 (ENSG00000162510), COL6A3 (ENSG00000163359), VWA2 (ENSG00000165816), COL6A5 (ENSG00000172752), VWA1 (ENSG00000179403), COL14A1 (ENSG00000187955), VIT (ENSG00000205221), COL6A6 (ENSG00000206384)

Protein

Protein identifiers

Collagen alpha-1(XII) chain — Q99715 (reviewed: Q99715)

All UniProt accessions (5): Q99715, D6RGG3, H0Y4P7, H0Y5N9, H0Y991

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Trimer of identical chains each containing 190 kDa of non-triple-helical sequences.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Found in collagen I-containing tissues: both isoform 1 and isoform 2 appear in amnion, chorion, skeletal muscle, small intestine, and in cell culture of dermal fibroblasts, keratinocytes and endothelial cells. Only isoform 2 is found in lung, placenta, kidney and a squamous cell carcinoma cell line. Isoform 1 is also present in the corneal epithelial Bowman’s membrane (BM) and the interfibrillar matrix of the corneal stroma, but it is not detected in the limbal BM.

Post-translational modifications. The triple-helical tail is stabilized by disulfide bonds at each end. Hydroxylation on proline residues within the sequence motif, GXPG, is most likely to be 4-hydroxy as this fits the requirement for 4-hydroxylation in vertebrates. Isoform 1 O-glycosylation; glycosaminoglycan of chondroitin-sulfate type.

Disease relevance. Ullrich congenital muscular dystrophy 2 (UCMD2) [MIM:616470] A form of Ullrich congenital muscular dystrophy, a disease characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis (rough skin). More severely affected patients manifest at birth and never achieve independent ambulation, while patients with milder phenotypes might maintain ambulation into adulthood. UCMD2 is a severe, autosomal recessive form with onset at birth. The disease is caused by variants affecting the gene represented in this entry. Bethlem myopathy 2 (BTHLM2) [MIM:616471] A form of Bethlem myopathy, a slowly progressive muscular dystrophy characterized by joint contractures, most frequently affecting the elbows and ankles, and muscle weakness and wasting involving the proximal and extensor muscles more than the distal and flexor ones. The clinical onset more often occurs in childhood or adulthood, but it can be prenatal with decreased fetal movements or neonatal with hypotonia. The hallmark of Bethlem myopathy is long finger flexion contractures. BTHLM2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the fibril-associated collagens with interrupted helices (FACIT) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99715-1	1, Long	yes
Q99715-2	2, Short
Q99715-4	4

RefSeq proteins (6): NP_001411042, NP_001411043, NP_001411044, NP_001411045, NP_004361, NP_542376 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR003961	FN3_dom	Domain
IPR008160	Collagen	Repeat
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR048287	TSPN-like_N	Domain
IPR050525	ECM_Assembly_Org	Family

Pfam: PF00041, PF00092, PF01391

UniProt features (105 total): domain 27, sequence conflict 17, modified residue 14, compositionally biased region 11, region of interest 10, sequence variant 10, glycosylation site 9, short sequence motif 3, splice variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9UFG	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

No AlphaFold model available for Q99715 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (14): 2944, 2947, 2950, 2959, 2965, 2968, 2971, 2983, 3000, 3003, 3014, 3023, 3026, 3029

Glycosylation sites (9): 329, 700, 798, 889, 981, 1763, 2206, 2528, 2679

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-8948216	Collagen chain trimerization

MSigDB gene sets: 428 (showing top): TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, WANG_CLIM2_TARGETS_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, NKX25_02, GOCC_COLLAGEN_TRIMER, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, ACTGCAG_MIR173P, AAAYRNCTG_UNKNOWN, BILD_HRAS_ONCOGENIC_SIGNATURE, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, IRF7_01

GO Biological Process (4): cell adhesion (GO:0007155), collagen fibril organization (GO:0030199), endodermal cell differentiation (GO:0035987), tissue development (GO:0009888)

GO Molecular Function (2): extracellular matrix structural constituent conferring tensile strength (GO:0030020), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), collagen type XII trimer (GO:0005595), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), extracellular vesicle (GO:1903561), collagen trimer (GO:0005581)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Collagen formation	2
Degradation of the extracellular matrix	1
Collagen biosynthesis and modifying enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
extracellular matrix organization	1
endoderm formation	1
cell differentiation	1
anatomical structure development	1
extracellular matrix structural constituent	1
binding	1
cellular anatomical structure	1
FACIT collagen trimer	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
extracellular vesicle	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

2108 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL12A1	LAMA2	P24043	734
COL12A1	BGN	P13247	660
COL12A1	LAMC1	P11047	657
COL12A1	LUM	P51884	640
COL12A1	LAMB1	P07942	634
COL12A1	LAMA5	O15230	624
COL12A1	THBS2	P35442	613
COL12A1	ITGA3	P26006	600
COL12A1	COL5A2	P05997	597
COL12A1	VCAN	P13611	581
COL12A1	COL1A1	P02452	565
COL12A1	COL6A3	P12111	560
COL12A1	PLOD2	O00469	558
COL12A1	COL6A1	P12109	556
COL12A1	COL1A2	P02464	548

IntAct

55 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
P4HA2	P4HB	psi-mi:“MI:0914”(association)	0.740
MMP9	TIMP1	psi-mi:“MI:0914”(association)	0.640
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
MMP2	COL4A1	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
PLOD3	PLOD2	psi-mi:“MI:0914”(association)	0.530
CNPY3	LRIG2	psi-mi:“MI:0914”(association)	0.530
LAIR2	LAMA5	psi-mi:“MI:0914”(association)	0.530
	TK2	psi-mi:“MI:0915”(physical association)	0.400
COL12A1		psi-mi:“MI:0915”(physical association)	0.370
SFTPA2	PRPSAP2	psi-mi:“MI:0914”(association)	0.350
C1QTNF1	PLOD2	psi-mi:“MI:0914”(association)	0.350
LAIR2	PLOD3	psi-mi:“MI:0914”(association)	0.350
MMP2	PLOD3	psi-mi:“MI:0914”(association)	0.350
LYZL2	POTEF	psi-mi:“MI:0914”(association)	0.350
EMID1	POTEF	psi-mi:“MI:0914”(association)	0.350
FSTL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
HHIPL1	POLRMT	psi-mi:“MI:0914”(association)	0.350
C1QTNF9B	RTCA	psi-mi:“MI:0914”(association)	0.350
C1QB	MANBA	psi-mi:“MI:0914”(association)	0.350
LAIR2	AGRN	psi-mi:“MI:0914”(association)	0.350
PLOD1	PLOD2	psi-mi:“MI:0914”(association)	0.350
COLGALT2	PLOD2	psi-mi:“MI:0914”(association)	0.350
COL10A1	PLOD2	psi-mi:“MI:0914”(association)	0.350
COL8A2	PLOD2	psi-mi:“MI:0914”(association)	0.350
ADIPOQ	PLOD2	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): COL12A1 (Affinity Capture-MS), COL12A1 (Synthetic Lethality), COL12A1 (Affinity Capture-MS), COL12A1 (Affinity Capture-MS), COL12A1 (Affinity Capture-MS), COL12A1 (Proximity Label-MS), COL12A1 (Affinity Capture-RNA), COL12A1 (Proximity Label-MS), COL12A1 (Two-hybrid), COL12A1 (Two-hybrid), COL12A1 (Reconstituted Complex), COL12A1 (Affinity Capture-MS), COL12A1 (Affinity Capture-MS), COL12A1 (Affinity Capture-MS), COL12A1 (Affinity Capture-MS)

ESM2 similar proteins: A2A863, A2AX52, A6H584, A6NMZ7, A8TX70, E1BMV3, O00339, O02668, O08746, O42422, P00751, P04186, P05099, P06681, P12111, P13944, P15989, P19823, P21180, P21941, P26007, P26008, P51942, P54759, P81187, Q03710, Q0V8S9, Q0VCM5, Q15375, Q21540, Q29052, Q3SYW2, Q60847, Q61702, Q61739, Q61772, Q64632, Q6DCQ6, Q6Q473, Q801S8

Diamond homologs: A0A1D5NSM8, A0JNA2, A2AVA0, A2AX52, D3YXF5, O02839, O19063, O35764, O43405, O70340, O76536, O89029, O95502, O96530, P02741, P02743, P06205, P06206, P06207, P06681, P07202, P07629, P08607, P09871, P0C6B8, P10643, P12246, P13944, P14151, P14847, P15697, P18337, P23680, P32018, P47970, P47971, P47972, P48199, P49254, P49262

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COL12A1	up-regulates	ECM_synthesis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 71 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Collagen biosynthesis and modifying enzymes	9	30.7×	2e-09
Collagen degradation	5	17.6×	1e-03
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	6	10.4×	2e-03
Post-translational protein phosphorylation	5	10.0×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
glycoprotein catabolic process	5	84.9×	1e-06
collagen fibril organization	5	18.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

4077 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	65
Uncertain significance	1999
Likely benign	1382
Benign	155

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069771	NM_004370.6(COL12A1):c.8571del (p.Pro2858fs)	Pathogenic
1070407	NM_004370.6(COL12A1):c.7085del (p.Gln2362fs)	Pathogenic
1073075	NC_000006.11:g.(?75796253)(75912518_?)del	Pathogenic
1215037	NM_004370.6(COL12A1):c.5794+2T>A	Pathogenic
1395130	NM_004370.6(COL12A1):c.27_42del (p.Ala10fs)	Pathogenic
1444852	NM_004370.6(COL12A1):c.6737_6812del (p.Gln2246fs)	Pathogenic
1455959	NC_000006.11:g.(?75855798)(75861023_?)del	Pathogenic
1459613	NC_000006.11:g.(?75833026)(75912508_?)del	Pathogenic
1986717	NM_004370.6(COL12A1):c.4924G>T (p.Glu1642Ter)	Pathogenic
2012070	NM_004370.6(COL12A1):c.8577+1del	Pathogenic
2017034	NM_004370.6(COL12A1):c.4231_4232del (p.Ser1411fs)	Pathogenic
2024721	NM_004370.6(COL12A1):c.5823del (p.Val1942fs)	Pathogenic
204294	NM_004370.6(COL12A1):c.7840+1G>A	Pathogenic
204296	NM_004370.6(COL12A1):c.8357G>A (p.Gly2786Asp)	Pathogenic
2048520	NM_004370.6(COL12A1):c.6094A>T (p.Arg2032Ter)	Pathogenic
2065481	NM_004370.6(COL12A1):c.7377del (p.Val2460fs)	Pathogenic
2078625	NM_004370.6(COL12A1):c.8759_8762del (p.Met2920fs)	Pathogenic
2098502	NM_004370.6(COL12A1):c.4245T>A (p.Tyr1415Ter)	Pathogenic
2112585	NM_004370.6(COL12A1):c.8100+2T>G	Pathogenic
2133985	NM_004370.6(COL12A1):c.4282C>T (p.Gln1428Ter)	Pathogenic
2505465	NM_004370.6(COL12A1):c.8329G>C (p.Gly2777Arg)	Pathogenic
2505466	NG_042181.1:(g.89607_91434)_(105703_107097)del	Pathogenic
2506378	NM_004370.6(COL12A1):c.8319+1G>T	Pathogenic
2506379	NM_004370.6(COL12A1):c.6061C>T (p.Arg2021Ter)	Pathogenic
2572588	NM_004370.6(COL12A1):c.2252T>G (p.Leu751Ter)	Pathogenic
2637720	NM_004370.6(COL12A1):c.4186C>T (p.Arg1396Ter)	Pathogenic
2926367	NM_004370.6(COL12A1):c.8366del (p.Gly2789fs)	Pathogenic
2926409	NM_004370.6(COL12A1):c.54del (p.Ser19fs)	Pathogenic
2944361	NM_004370.6(COL12A1):c.7637del (p.Ser2546fs)	Pathogenic
2945306	NM_004370.6(COL12A1):c.8108del (p.Ile2703fs)	Pathogenic

SpliceAI

8834 predictions. Top by Δscore:

Variant	Effect	Δscore
6:75089101:CCTA:C	donor_loss	1.0000
6:75089102:CTAC:C	donor_loss	1.0000
6:75089103:TACCT:T	donor_loss	1.0000
6:75089104:A:AC	donor_gain	1.0000
6:75089104:A:C	donor_loss	1.0000
6:75089105:C:CC	donor_gain	1.0000
6:75089105:C:CG	donor_loss	1.0000
6:75089170:CAAAC:C	acceptor_gain	1.0000
6:75089173:AC:A	acceptor_gain	1.0000
6:75089174:CC:C	acceptor_gain	1.0000
6:75089175:C:CC	acceptor_gain	1.0000
6:75089175:CTAAG:C	acceptor_loss	1.0000
6:75090105:CCTA:C	donor_loss	1.0000
6:75090106:CTACC:C	donor_loss	1.0000
6:75090107:TA:T	donor_loss	1.0000
6:75090108:ACC:A	donor_loss	1.0000
6:75090109:CCT:C	donor_gain	1.0000
6:75090135:C:A	donor_gain	1.0000
6:75090294:CTGAC:C	acceptor_gain	1.0000
6:75090295:TGAC:T	acceptor_gain	1.0000
6:75090296:GAC:G	acceptor_gain	1.0000
6:75090297:AC:A	acceptor_gain	1.0000
6:75090298:CC:C	acceptor_gain	1.0000
6:75090299:C:CC	acceptor_gain	1.0000
6:75091322:CCA:C	donor_gain	1.0000
6:75091328:A:AC	donor_gain	1.0000
6:75091329:T:C	donor_gain	1.0000
6:75091389:CCT:C	acceptor_gain	1.0000
6:75091391:T:C	acceptor_gain	1.0000
6:75091391:T:TC	acceptor_gain	1.0000

AlphaMissense

19811 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:75117398:A:C	C2501W	1.000
6:75117399:C:G	C2501S	1.000
6:75117399:C:T	C2501Y	1.000
6:75117400:A:G	C2501R	1.000
6:75117400:A:T	C2501S	1.000
6:75117414:A:G	L2496P	1.000
6:75119096:T:A	D2434V	1.000
6:75119108:A:T	V2430D	1.000
6:75119177:A:G	L2407P	1.000
6:75121392:C:A	W2332C	1.000
6:75121392:C:G	W2332C	1.000
6:75121394:A:G	W2332R	1.000
6:75121394:A:T	W2332R	1.000
6:75121396:G:A	S2331F	1.000
6:75121396:G:T	S2331Y	1.000
6:75121397:A:G	S2331P	1.000
6:75121402:T:A	D2329V	1.000
6:75121402:T:G	D2329A	1.000
6:75121403:C:A	D2329Y	1.000
6:75121403:C:G	D2329H	1.000
6:75121411:A:G	F2326S	1.000
6:75137514:A:G	W1773R	1.000
6:75137514:A:T	W1773R	1.000
6:75148432:A:G	W1405R	1.000
6:75148432:A:T	W1405R	1.000
6:75152424:C:A	W1208C	1.000
6:75152424:C:G	W1208C	1.000
6:75152426:A:G	W1208R	1.000
6:75152426:A:T	W1208R	1.000
6:75152434:T:A	D1205V	1.000

dbSNP variants (sampled 300 via entrez): RS1000019982 (6:75193518 A>G), RS1000029178 (6:75135235 C>A,T), RS1000077313 (6:75143181 T>C), RS1000097849 (6:75149885 C>A,G), RS1000153005 (6:75128121 T>C), RS1000191333 (6:75185019 C>G,T), RS1000239584 (6:75121020 T>C), RS1000246992 (6:75204785 C>T), RS1000269370 (6:75161478 A>G), RS1000327124 (6:75088371 G>A), RS1000403174 (6:75107093 C>T), RS1000412037 (6:75185981 G>A), RS1000415432 (6:75098415 A>T), RS1000440882 (6:75201907 C>A,T), RS1000450277 (6:75159723 A>C)

Disease associations

OMIM: gene MIM:120320 | disease phenotypes: MIM:616470, MIM:616471, MIM:254090, MIM:613090, MIM:158810, MIM:130000, MIM:613763

GenCC curated gene-disease

Disease	Classification	Inheritance
Bethlem myopathy 2	Strong	Autosomal dominant
Ullrich congenital muscular dystrophy 2	Strong	Autosomal recessive
Bethlem myopathy	Supportive	Autosomal dominant
Ullrich congenital muscular dystrophy	Supportive	Autosomal dominant

Mondo (12): Ullrich congenital muscular dystrophy 2 (MONDO:0014654), Bethlem myopathy 2 (MONDO:0034022), Ullrich congenital muscular dystrophy 1A (MONDO:0009681), Bartter disease type 4B (MONDO:0000909), Bethlem myopathy (MONDO:0008029), neurodevelopmental disorder (MONDO:0700092), Bethlem myopathy 1A (MONDO:0024530), Ehlers-Danlos syndrome (MONDO:0020066), cataract 16 multiple types (MONDO:0013411), Ullrich congenital muscular dystrophy (MONDO:0000355), Charcot-Marie-Tooth disease type 2 (MONDO:0018993), (MONDO:0014655)

Orphanet (10): Myopathic Ehlers-Danlos syndrome (Orphanet:536516), Bethlem muscular dystrophy (Orphanet:610), Ullrich congenital muscular dystrophy (Orphanet:75840), Bartter syndrome (Orphanet:112), Ehlers-Danlos syndrome (Orphanet:98249), Early onset non-syndromic cataract (Orphanet:91492), Early-onset partial cataract (Orphanet:98992), Early-onset posterior polar cataract (Orphanet:98993), Early-onset zonular cataract (Orphanet:98995), Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746)

HPO phenotypes

109 total (30 of 109 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000174	Abnormal palate morphology
HP:0000218	High palate
HP:0000347	Micrognathia
HP:0000467	Neck muscle weakness
HP:0000470	Short neck
HP:0000473	Torticollis
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000592	Blue sclerae
HP:0000767	Pectus excavatum
HP:0000962	Hyperkeratosis
HP:0000974	Hyperextensible skin
HP:0000977	Soft skin
HP:0000980	Pallor
HP:0001058	Poor wound healing
HP:0001073	Cigarette-paper scars
HP:0001075	Atrophic scars
HP:0001181	Adducted thumb
HP:0001182	Tapered finger
HP:0001220	Interphalangeal joint contracture of finger
HP:0001238	Slender finger
HP:0001239	Wrist flexion contracture
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001319	Neonatal hypotonia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003998_20	Joint mobility (Beighton score)	3.000000e-07
GCST004025_20	Systemic juvenile idiopathic arthritis	3.000000e-06
GCST005667_9	Central corneal thickness	2.000000e-08
GCST90000654_38	Central corneal thickness	4.000000e-13
GCST90013442_9	Keratoconus	3.000000e-25

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007905	joint hypermobility measurement
EFO:0005213	central corneal thickness

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D065886	Neurodevelopmental Disorders	F03.625
C535436	Bethlem myopathy (supp.)
C565134	Cataract, Posterior Polar, 2 (supp.)
C537521	Scleroatonic muscular dystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

83 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Benzo(a)pyrene	affects methylation, increases expression, increases methylation, increases mutagenesis	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases stability, affects expression	4
Estradiol	decreases reaction, increases expression, decreases expression, affects cotreatment	4
methylmercuric chloride	increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
bisphenol F	decreases expression, increases expression, affects cotreatment	2
bisphenol A	increases expression	2
manganese chloride	decreases expression, increases abundance, affects cotreatment	2
mercuric bromide	increases expression, affects cotreatment	2
Resveratrol	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation	2
Cadmium	increases expression, decreases reaction, increases abundance, increases palmitoylation	2
Dexamethasone	decreases expression, affects cotreatment	2
Doxorubicin	decreases expression	2
Fluorouracil	decreases expression	2
Manganese	decreases expression, increases abundance, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
Particulate Matter	decreases expression, increases abundance	2
geldanamycin	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
titanium dioxide	affects binding, increases expression	1
VX-agent	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
potassium chromate(VI)	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8J6	Ubigene HCT 116 COL12A1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

256 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT01438788	PHASE2	COMPLETED	Low Protein Diet in Patients With Collagen VI Related Myopathies
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01895283	Not specified	COMPLETED	The Effect of Aerobic Exercise, on Fitness and Functional Muscle Strength, in Patients With Muscular Dystrophy
NCT03693898	Not specified	UNKNOWN	MR in Patients With Collagen VI Related Myopathies
NCT04020159	Not specified	UNKNOWN	Global Registry for COL6-related Dystrophies
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study