ABCB6
protein-codingATP binding cassette subfamily B member 6 (Langereis blood group), the group of ATP binding cassette subfamily B|Blood group antigens
Gene summary
This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. ABC proteins transport various molecules across extra- and intra-cellular membranes. This protein is a member of the heavy metal importer subfamily and plays a role in porphyrin transport. This gene is the molecular basis of the Langereis (Lan) blood group antigen and mutations in this gene underlie familial pseudohyperkalemia and dyschromatosis universalis hereditaria. [provided by RefSeq, Mar 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014169
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013783
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013783
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013783
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014169
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012204
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014169
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013783
Submitter: ClinGen
*ABCB6* was first reported in relation to autosomal dominant isolated microphthalmia with coloboma in 2012 (Wang et al., PMID: 22226084). At least three missense variants have been reported in humans. Evidence supporting this gene disease relationship includes case-level data, segregation data, and experimental data. Variants in *ABCB6* have been reported in individuals with the following disease entities: Dyschromatosis universalis hereditaria, Isolated microphthalmia with coloboma, and Familial pseudohyperkalemia. Further, biallelic truncating variants affecting *ABCB6* are responsible for the Lan(-) blood group (MIM#111600). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and no consistent mechanism of disease. Therefore, the following disease entities have been split and curated separately: Dyschromatosis universalis hereditaria (MIM#615402), Isolated microphthalmia with coloboma (MIM#614497). Familial pseudohyperkalemia (MIM#609153) has not been curated at this time as it is an asymptomatic condition apparent only in refrigerated blood samples due to temperature-dependent leak of potassium across the cell membrane of erythrocytes. Three missense variants in *ABCB6* have been reported in association with isolated microphthalmia with coloboma in three probands across two publications (PMID: 22226084; 24281366). Co-segregation with disease was observed in one family (PMID: 22226084). The mechanism of disease is currently unknown. This gene-disease relationship is supported by a zebrafish model (PMID: 22226084). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on 22MAR2024 (SOP 10).
Inheritance Pattern: AD
Disease ID:MONDO:0012204
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0000170
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014169
Submitter: ClinGen
*ABCB6* was first reported in relation to autosomal dominant dyschromatosis universalis hereditaria (DUH) in 2013 (Zhang et al., PMID: 23519333). DUH is characterized by the presence of hypo- and hyperpigmented skin macules on the trunk, limbs, and face. At least 9 missense variants have been reported in humans. Evidence supporting this gene disease relationship includes case-level data, segregation data, and experimental data. Variants in *ABCB6* have been reported in individuals with the following disease entities: Dyschromatosis universalis hereditaria, Isolated microphthalmia with coloboma, and Familial pseudohyperkalemia. Further, biallelic truncating variants affecting *ABCB6* are responsible for the Lan(-) blood group (MIM#111600). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and no consistent mechanism of disease. Therefore, the following disease entities have been split and curated separately: Dyschromatosis universalis hereditaria (MIM#615402), Isolated microphthalmia with coloboma (MIM#614497). Familial pseudohyperkalemia (MIM#609153) has not been curated at this time as it is an asymptomatic condition apparent only in refrigerated blood samples due to temperature-dependent leak of potassium across the cell membrane of erythrocytes. Nine missense variants in *ABCB6* have been reported in association with DUH in ten probands across six publications (PMID: 23519333; 24224009; 24498303; 25288164; 35024399; 30430618). Co-segregation with disease was observed in five families (PMID: 23519333; 24224009; 24498303; 25288164). The mechanism of disease is currently unknown. This gene-disease relationship is supported by expression studies, in vitro functional assays, and animal models (PMID: 23519333; 24498303; 29940187; 35461746). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was first approved by the ClinGen General Inborn Errors of Metabolism GCEP on March 22, 2024 (SOP 10). This gene-disease relationship was reapproved as moderate on June 12, 2026, after a literature search and discussion with the GCEP experts revealed no additional data (SOP 12).
Inheritance Pattern: AD
Disease ID:MONDO:0000736
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Hematologic; Ophthalmologic
Intervention: Hematologic
Rationale: Variants related to Familial pseudohyperkalemia may be important related to transfusion management; Variants associated with a blood group may be important in specific situations (eg, related to transfusion)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ABCB6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005689.4. 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 | 4 | 41 | 1 | 46 | ||
| missense | 6 | 2 | 187 | 21 | 2 | 218 |
| nonsense | 1 | 7 | 8 | |||
| start loss | 0 | |||||
| frameshift | 2 | 12 | 1 | 15 | ||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 7 | |||
| Total | 6 | 6 | 216 | 63 | 3 | 294 |
Highest pathogenic variant AF is 0.000024783914
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005680.1 | 19 | MANE Select | |
| Ensembl | ENSP00000265316.3 | 19 | MANE Select | |
| RefSeq | NP_001336757.1 | 18 | Standard | |
| Ensembl | ENSP00000295750.5 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| abcb6a | Danio rerio | Structure: pupil Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- ABC transporters - Homo sapiens (human)
- Transport of small molecules
- ABC-family proteins mediated transport
- Mitochondrial ABC transporters
Biological Process
- porphyrin-containing compound biosynthetic process
- cellular iron ion homeostasis
- brain development
- heme transport
- skin development
Molecular Function
- ATP binding
- heme transporter activity
- heme-transporting ATPase activity
- efflux transmembrane transporter activity
- heme binding
Cellular Component
- Golgi membrane
- nucleoplasm
- mitochondrion
- mitochondrial envelope
- mitochondrial outer membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000265316
- Coding exons
- 19
- Length
- 9223
- Individuals with no LoFs
- 125411
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 337
- Defined
- 125748
- p
- 0.00134
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.139 | 507 | 498 | 1.02 | 0.0000299 | 5354 |
| Missense (PolyPhen) | 189 | 184.3 | 1.0255 | 2008 | ||
| Synonymous | -1.55 | 234 | 206 | 1.14 | 0.0000125 | 1788 |
| Loss of Function | 1.68 | 35 | 47.5 | 0.737 | 0.00000264 | 455 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0018 | 0.0018 | notable |
| Latino/Admixed American | 0.0032 | 0.0032 | notable |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.0019 | 0.0019 | notable |
| Finnish | 0.0013 | 0.0012 | notable |
| European (Non-Finnish) | 0.0010 | 0.00093 | notable |
| South Asian | 0.00080 | 0.00072 | rare |
| Other | 0.0012 | 0.0011 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds heme and porphyrins and functions in their ATP- dependent uptake into the mitochondria. Plays a crucial role in heme synthesis. {ECO:0000269|PubMed:10837493, ECO:0000269|PubMed:17006453}.;
- Disease
- DISEASE: Microphthalmia, isolated, with coloboma, 7 (MCOPCB7) [MIM:614497]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:22226084}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dyschromatosis universalis hereditaria 3 (DUH3) [MIM:615402]: An autosomal dominant pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body, that appear in infancy or early childhood. The trunk and extremities are the dominant sites of abnormal pigmentation. Facial lesions can be seen in 50% of affected individuals, but involvement of palms and soles is unusual. Abnormalities of hair and nails have also been reported. Dyschromatosis universalis hereditaria may be associated with abnormalities of dermal connective tissue, nerve tissue, or other systemic complications. {ECO:0000269|PubMed:23519333, ECO:0000269|PubMed:24224009, ECO:0000269|PubMed:24498303, ECO:0000269|PubMed:25288164}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pseudohyperkalemia, familial, 2, due to red cell leak (PSHK2) [MIM:609153]: A dominantly inherited condition characterized by increased serum potassium levels, measured in whole-blood specimens stored at or below room temperature. This condition is not accompanied by clinical symptoms or biological signs except for borderline abnormalities of red cell shape. {ECO:0000269|PubMed:23180570, ECO:0000269|PubMed:24947683}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.165
- RVIS EVS
- -0.37
- RVIS percentile EVS
- 28.26
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.558
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |