ABCC6
protein-codingATP binding cassette subfamily C member 6, the group of ATP binding cassette subfamily C
Gene summary
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008]
- ARA
- PXE
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~74.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: SD
Disease ID:MONDO:0100091
Submitter: ClinGen
ATP-binding cassette subfamily C, member 6 (*ABCC6*) was first reported in relation to autosomal dominant/autosomal recessive pseudoxanthoma elasticum (PXE) in 2000 by three research groups (Ringpfeil et al., PMID 10811882; Bergen et al., PMID 10835643; Le Saux et al., PMID 10835642). Pseudoxanthoma elasticum is characterized by calcifications that manifest subcutaneously in yellow papules, in the eyes as angioid streaks or in arterial walls. A more severe presentation of disease was first reported in 2012 as autosomal recessive generalized arterial calcification of infancy (GACI) which had previously only been linked to biallelic variation in *ENPP1* (Nitschke et al., PMID 22200248). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism or phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity, pseudoxanthoma elasticum (AR; OMIM:264800), generalized arterial calcification of infancy 2 (AR; OMIM:614473) and forme fruste pseudoxanthoma elasticum (AD; OMIM:177850). The association of monoallelic *ABCC6* variation and PXE is debated in the literature, however, heterozygous variant carriers have been documented with clinical and/or histopathological indications of PXE as well as a potential for increased cardiovascular calcification or stroke (PMIDs 40725385, 29722917). 18 variants (3 nonsense, 6 missense, 6 frameshift, 2 splice-site, 1 multi-exon deletion) that have been reported in 17 probands in 4 publications (PMIDs: 10811882, 10835643, 22209248, 29709427) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, rescue in a mouse model, and biochemical evidence (PMIDs: 16135817, 36769695, 28416300). Biallelic knockout of *ABCC6* in mouse models recapitulates the calcification phenotype seen in humans as well as the reduction in circulating inorganic pyrophosphate (ppi) which has been reported as an inhibitor of calcification. It was also shown that while there is a significant reduction in ppi between controls and PXE patients, there was not a connection between the severity of phenotypes and the measured ppi levels. In summary, there is definitive evidence supporting the relationship between *ABCC6* and semidominant *ABCC6*-related generalized arterial calcification. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Neurovascular Disease GCEP on the meeting date October 22, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009925
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0009925
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009925
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013768
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0009925
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009925
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0009925
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018870
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013768
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Dermatologic; Hematologic; Ophthalmologic
Intervention: Cardiovascular; Hematologic; Ophthalmologic
Rationale: Preventive measures (eg, weight control, avoidance of smoking, and medical management of hypertension and hypercholesterolemia) related to cardiovascular risk factors may be beneficial by decreasing contributory factors related to atherosclerosis; Awareness may allow surveillance for and early detection and treatment of cardiovascular (eg, surgical interventions related to vascular disease) and hematologic manifestations (eg, interventions related to GI bleeding); Standard treatment for macular degeneration (including intraocular injection of anti-angiogenic drugs) may be beneficial, and awareness of ophthalmologic aspects may allow early detection and treatment; Circumstances such as contact sports and the use of medications that increase the risk of GI bleeding should be avoided
Comments: In recessive forms, heterozygotes may have mild manifestations; Digenic inheritance (with GGCX) has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ABCC6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001171.6. 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 | 1 | 20 | 418 | 3 | 442 | |
| missense | 31 | 100 | 686 | 63 | 5 | 885 |
| nonsense | 27 | 41 | 1 | 69 | ||
| start loss | 0 | |||||
| frameshift | 40 | 62 | 5 | 107 | ||
| splice donor/acceptor (+/-2bp) | 6 | 39 | 10 | 55 | ||
| Total | 105 | 242 | 722 | 481 | 8 | 1558 |
Highest pathogenic variant AF is 0.0016128413
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001162.5 | 31 | MANE Select | |
| Ensembl | ENSP00000205557.7 | 31 | MANE Select | |
| RefSeq | NP_001072996.1 | 2 | Standard | |
| RefSeq | NP_001338729.1 | 29 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| abcc6b.2 | Danio rerio | Structure: whole organism Quality: dead abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- ABC transporters - Homo sapiens (human)
- Photodynamic therapy-induced NFE2L2 (NRF2) survival signaling
- Transport of small molecules
- ABC-family proteins mediated transport
Biological Process
- visual perception
- response to drug
- transmembrane transport
- ATP hydrolysis coupled anion transmembrane transport
Molecular Function
- transporter activity
- ATP binding
- ATPase activity, coupled to transmembrane movement of substances
- ATPase-coupled anion transmembrane transporter activity
Cellular Component
- nucleus
- vacuolar membrane
- endoplasmic reticulum membrane
- plasma membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000205557
- Coding exons
- 31
- Length
- 74595
- Individuals with no LoFs
- 125040
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 708
- Defined
- 125748
- p
- 0.00282
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.09 | 926 | 837 | 1.11 | 0.0000531 | 9576 |
| Missense (PolyPhen) | 222 | 216.8 | 1.024 | 2380 | ||
| Synonymous | -1.09 | 391 | 365 | 1.07 | 0.0000239 | 3223 |
| Loss of Function | 1.36 | 60 | 72.5 | 0.828 | 0.00000361 | 781 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0011 | 0.0011 | notable |
| Latino/Admixed American | 0.0012 | 0.0012 | notable |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.0044 | 0.0044 | notable |
| Finnish | 0.0043 | 0.0043 | notable |
| European (Non-Finnish) | 0.0038 | 0.0038 | notable |
| South Asian | 0.00092 | 0.00091 | rare |
| Other | 0.0028 | 0.0028 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Isoform 1: May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Transports glutathione conjugates as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS). {ECO:0000269|PubMed:11880368}.;
- Disease
- DISEASE: Pseudoxanthoma elasticum (PXE) [MIM:264800]: A multisystem disorder characterized by accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Burch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d'orange, angioid streaks, and choroidal neovascularizations, of the skin including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings. {ECO:0000269|PubMed:10811882, ECO:0000269|PubMed:10835642, ECO:0000269|PubMed:10954200, ECO:0000269|PubMed:11427982, ECO:0000269|PubMed:11536079, ECO:0000269|PubMed:11702217, ECO:0000269|PubMed:11880368, ECO:0000269|PubMed:15086542, ECO:0000269|PubMed:15098239, ECO:0000269|PubMed:15459974, ECO:0000269|PubMed:16086317, ECO:0000269|PubMed:17617515, ECO:0000269|PubMed:19339160, ECO:0000269|PubMed:20034067, ECO:0000269|PubMed:25615550}. Note=The disease is caused by mutations affecting the gene represented in this entry. Homozygous or compound heterozygous ABCC6 mutations have been found in the overwhelming majority of cases. Individuals carrying heterozygous mutations express limited manifestations of the pseudoxanthoma elasticum phenotype.; DISEASE: Arterial calcification of infancy, generalized, 2 (GACI2) [MIM:614473]: A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure. {ECO:0000269|PubMed:22209248}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0194
- RVIS EVS
- 0.63
- RVIS percentile EVS
- 83.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.159
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |