GeneBe

ABCA4

ATP binding cassette subfamily A member 4, the group of ATP binding cassette subfamily A

Basic information

Region (hg38): 1:93992834-94121148

Previous symbols: [ "STGD1", "ABCR", "RP19", "STGD" ]

Links

ENSG00000198691 ∙ NCBI:24 ∙ OMIM:601691 ∙ HGNC:34 ∙ Uniprot:P78363 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • severe early-childhood-onset retinal dystrophy (Definitive), mode of inheritance: AR
  • cone-rod dystrophy 3 (Definitive), mode of inheritance: AR
  • severe early-childhood-onset retinal dystrophy (Definitive), mode of inheritance: AR
  • Stargardt disease (Supportive), mode of inheritance: AD
  • retinitis pigmentosa (Supportive), mode of inheritance: AD
  • cone-rod dystrophy (Supportive), mode of inheritance: AD
  • cone-rod dystrophy 3 (Strong), mode of inheritance: AR
  • retinitis pigmentosa 19 (Strong), mode of inheritance: AR
  • severe early-childhood-onset retinal dystrophy (Strong), mode of inheritance: AR
  • ABCA4-related retinopathy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Cone-rod dystrophy 3; Retinitis pigmentosa 19; Stargardt disease 1; Retinal dystrophy, early-onset severe; Fundus flavimaculatus; Macular degeneration, age-related, 2AD/ARGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingOphthalmologic9054934; 9466990; 9425888; 9781034; 10396622; 10442900; 10874631; 10396622; 11818392; 12515255; 12796258; 16896346; 16682602; 11385708; 21510770; 21786275; 22229821; 22312191; 22328824; 22395892; 22661473; 22863181; 23096905

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ABCA4 gene.

  • not provided (599 variants)
  • Severe early-childhood-onset retinal dystrophy (99 variants)
  • Retinal dystrophy (79 variants)
  • Stargardt disease (41 variants)
  • Retinitis pigmentosa 19 (19 variants)
  • Retinitis pigmentosa (18 variants)
  • Age related macular degeneration 2 (13 variants)
  • Cone-rod dystrophy 3 (13 variants)
  • Stargardt disease 3 (12 variants)
  • Cone-rod dystrophy (11 variants)
  • ABCA4-related disorder (6 variants)
  • Isolated macular dystrophy (4 variants)
  • Macular dystrophy (4 variants)
  • Cone dystrophy (3 variants)
  • See cases (3 variants)
  • Age related macular degeneration 2;Cone-rod dystrophy 3;Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19 (3 variants)
  • Autosomal recessive retinitis pigmentosa (3 variants)
  • maculopathy (3 variants)
  • Generalized choriocapillaris dystrophy (2 variants)
  • Macular degeneration;Visual loss;Blindness (1 variants)
  • not specified (1 variants)
  • Retinal atrophy;Central scotoma;Visual impairment;Macular degeneration (1 variants)
  • Inborn genetic diseases (1 variants)
  • Abnormality of the eye (1 variants)
  • Cone-rod dystrophy 3;Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19 (1 variants)
  • Progressive cone dystrophy (without rod involvement) (1 variants)
  • Retinal dystrophy, early-onset severe (1 variants)
  • Severe early-childhood-onset retinal dystrophy;Stargardt disease (1 variants)
  • Retinitis pigmentosa 19;Cone-rod dystrophy 3;Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ABCA4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
1
clinvar
1
clinvar
19
clinvar
606
clinvar
15
clinvar
 642
missense
188
clinvar
366
clinvar
791
clinvar
24
clinvar
3
clinvar
 1372
nonsense
132
clinvar
28
clinvar
1
clinvar
 161
start loss
2
clinvar
2
clinvar
 4
frameshift
201
clinvar
39
clinvar
2
clinvar
 242
inframe indel
14
clinvar
4
clinvar
14
clinvar
 32
splice donor/acceptor (+/-2bp)
87
clinvar
61
clinvar
3
clinvar
 151
splice region
11
16
70
112
9
 218
non coding
12
clinvar
7
clinvar
29
clinvar
439
clinvar
175
clinvar
 662
Total 637 508 859 1069 193

Highest pathogenic variant AF is 0.000821

Variants in ABCA4

This is a list of pathogenic ClinVar variants found in the ABCA4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
1-93992865-T-C Macular degeneration • Stargardt Disease, Recessive • Retinitis Pigmentosa, Recessive • Cone-Rod Dystrophy, Recessive • ABCA4-related disorder Benign/Likely benign (May 08, 2021)298215
1-93992938-C-G Retinitis Pigmentosa, Recessive • Macular degeneration • Cone-Rod Dystrophy, Recessive • Stargardt Disease, Recessive • ABCA4-related disorder Conflicting classifications of pathogenicity (Jan 13, 2018)298216
1-93992953-A-G ABCA4-related disorder Uncertain significance (Jan 13, 2018)873737
1-93992983-G-T ABCA4-related disorder Uncertain significance (Mar 30, 2018)873738
1-93993009-T-A ABCA4-related disorder Uncertain significance (Jan 12, 2018)873739
1-93993090-G-A Retinitis Pigmentosa, Recessive • Stargardt Disease, Recessive • Macular degeneration • Cone-Rod Dystrophy, Recessive • ABCA4-related disorder Uncertain significance (Jan 12, 2018)298217
1-93993101-C-T Macular degeneration • Stargardt Disease, Recessive • Retinitis Pigmentosa, Recessive • Cone-Rod Dystrophy, Recessive • ABCA4-related disorder Conflicting classifications of pathogenicity (Jan 12, 2018)298218
1-93993103-C-T Stargardt Disease, Recessive • Cone-Rod Dystrophy, Recessive • Macular degeneration • Retinitis Pigmentosa, Recessive • ABCA4-related disorder Benign/Likely benign (Jul 05, 2018)298219
1-93993182-C-A Cone-Rod Dystrophy, Recessive • Retinitis Pigmentosa, Recessive • Macular degeneration • Stargardt Disease, Recessive • ABCA4-related disorder Likely benign (Apr 27, 2017)298220
1-93993211-G-T Macular degeneration • Stargardt Disease, Recessive • Cone-Rod Dystrophy, Recessive • Retinitis Pigmentosa, Recessive • ABCA4-related disorder Likely benign (Apr 27, 2017)298221
1-93993214-G-A ABCA4-related disorder Uncertain significance (Jan 12, 2018)874697
1-93993227-G-T ABCA4-related disorder • not specified Uncertain significance (Jan 13, 2018)874698
1-93993239-A-T Cone-rod dystrophy 3 Uncertain significance (-)916723
1-93993244-T-C Retinal dystrophy • Severe early-childhood-onset retinal dystrophy Pathogenic/Likely pathogenic (Mar 29, 2024)866510
1-93993244-T-G Pathogenic (Oct 06, 2023)1455137
1-93993251-G-A Likely benign (Aug 23, 2023)2873236
1-93993259-C-T Likely benign (Mar 11, 2021)1540238
1-93993260-A-G Likely benign (Sep 11, 2023)1988105
1-93993261-T-G Likely benign (Nov 05, 2023)2693426
1-93993327-G-A Benign (Nov 22, 2018)1297754
1-93993444-A-T Benign (Jul 14, 2018)1259702
1-93995982-G-A Benign (Jul 05, 2018)1248438
1-93996081-C-G not specified Benign (Mar 03, 2015)255927
1-93996098-A-T Likely benign (Apr 26, 2023)2859527
1-93996100-C-T Likely benign (May 09, 2023)2862772

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
ABCA4protein_codingprotein_codingENST00000370225 50128296
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
5.35e-480.0060712550802401257480.000955
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-0.65813061.24e+31.050.000074614895
Missense in Polyphen430459.990.934815686
Synonymous-1.575424971.090.00003194485
Loss of Function2.37891170.7630.000006241336

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.001440.00144
Ashkenazi Jewish0.0003000.000298
East Asian0.0009250.000925
Finnish0.0002310.000231
European (Non-Finnish)0.001060.00106
Middle Eastern0.0009250.000925
South Asian0.001870.00186
Other0.0005070.000489

dbNSFP

Source: dbNSFP

Function
FUNCTION: In the visual cycle, acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans- retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. May play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery. {ECO:0000269|PubMed:10075733}.;
Disease
DISEASE: Fundus flavimaculatus (FFM) [MIM:248200]: Autosomal recessive retinal disorder very similar to Stargardt disease. In contrast to Stargardt disease, FFM is characterized by later onset and slowly progressive course. {ECO:0000269|PubMed:11379881, ECO:0000269|PubMed:11385708, ECO:0000269|PubMed:9781034}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 2 (ARMD2) [MIM:153800]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:19028736, ECO:0000269|PubMed:9295268}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Cone-rod dystrophy 3 (CORD3) [MIM:604116]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:10958761, ECO:0000269|PubMed:11385708, ECO:0000269|PubMed:11527935}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 19 (RP19) [MIM:601718]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP19 is characterized by choroidal atrophy. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway
ABC transporters - Homo sapiens (human);Signaling by GPCR;Signal Transduction;The canonical retinoid cycle in rods (twilight vision);Transport of small molecules;ABC-family proteins mediated transport;G alpha (i) signalling events;Visual phototransduction;GPCR downstream signalling (Consensus)

Recessive Scores

pRec
0.388

Intolerance Scores

loftool
0.0107
rvis_EVS
0.74
rvis_percentile_EVS
86.31

Haploinsufficiency Scores

pHI
0.0992
hipred
N
hipred_score
0.448
ghis

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.704

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerHighMediumHigh

Mouse Genome Informatics

Gene name
Abca4
Phenotype
pigmentation phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; homeostasis/metabolism phenotype; immune system phenotype;

Gene ontology

Biological process
retinoid metabolic process;phospholipid transfer to membrane;lipid transport;visual perception;phototransduction, visible light;phospholipid translocation;photoreceptor cell maintenance;transmembrane transport
Cellular component
integral component of plasma membrane;membrane;intracellular membrane-bounded organelle;photoreceptor disc membrane
Molecular function
phospholipid-translocating ATPase activity;transporter activity;lipid transporter activity;eye pigment precursor transporter activity;ATP binding;phospholipid transporter activity;ATPase activity;ATPase activity, coupled to transmembrane movement of substances;phosphatidylethanolamine-translocating ATPase activity