ABCA4

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

Basic information

Region (hg38): 1:93992833-94121148

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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cone-rod dystrophy 3; Retinitis pigmentosa 19; Stargardt disease 1; Retinal dystrophy, early-onset severe; Fundus flavimaculatus; Macular degeneration, age-related, 2	AD/AR	General	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	Ophthalmologic	9054934; 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 (3061 variants)
• Retinal dystrophy (397 variants)
• Severe early-childhood-onset retinal dystrophy (384 variants)
• ABCA4-Related Disorders (212 variants)
• not specified (120 variants)
• Stargardt disease (110 variants)
• Retinitis Pigmentosa, Recessive (100 variants)
• Macular degeneration (99 variants)
• Cone-Rod Dystrophy, Recessive (99 variants)
• Stargardt Disease, Recessive (98 variants)
• Age related macular degeneration 2 (77 variants)
• Cone-rod dystrophy 3 (70 variants)
• Inborn genetic diseases (60 variants)
• Retinitis pigmentosa 19 (57 variants)
• Retinitis pigmentosa (44 variants)
• ABCA4-related condition (30 variants)
• Cone-rod dystrophy 3;Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19 (29 variants)
• Cone-rod dystrophy (26 variants)
• Macular dystrophy (18 variants)
• Autosomal recessive retinitis pigmentosa (9 variants)
• Isolated macular dystrophy (8 variants)
• Cone dystrophy (7 variants)
• Retinitis pigmentosa 19;Cone-rod dystrophy 3;Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy (5 variants)
• Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19;Age related macular degeneration 2;Cone-rod dystrophy 3 (5 variants)
• maculopathy (5 variants)
• Abnormal retinal morphology (4 variants)
• ABCA4-related retinopathy (4 variants)
• MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO (4 variants)
• Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy;Cone-rod dystrophy 3;Retinitis pigmentosa 19 (3 variants)
• Age related macular degeneration 2;Retinitis pigmentosa 19;Cone-rod dystrophy 3;Severe early-childhood-onset retinal dystrophy (3 variants)
• Generalized choriocapillaris dystrophy (3 variants)
• Severe early-childhood-onset retinal dystrophy;Cone-rod dystrophy 3;Age related macular degeneration 2;Retinitis pigmentosa 19 (3 variants)
• Abnormality of the eye (3 variants)
• Severe early-childhood-onset retinal dystrophy;Age related macular degeneration 2;Cone-rod dystrophy 3;Retinitis pigmentosa 19 (3 variants)
• Leber congenital amaurosis (2 variants)
• Benign concentric annular macular dystrophy (2 variants)
• Retinitis pigmentosa 19;Severe early-childhood-onset retinal dystrophy;Age related macular degeneration 2;Cone-rod dystrophy 3 (2 variants)
• Severe early-childhood-onset retinal dystrophy;Stargardt disease (2 variants)
• Retinal dystrophy, early-onset severe (2 variants)
• Vitreoretinopathy (2 variants)
• Stargardt disease 3 (2 variants)
• Retinopathy;Visual impairment (2 variants)
• Progressive cone dystrophy (without rod involvement) (2 variants)
• Peripheral neuropathy;Abnormal macular morphology (2 variants)
• Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19;Cone-rod dystrophy 3 (2 variants)
• Retinitis pigmentosa 1 (2 variants)
• Mandibulofacial dysostosis with mental deficiency (1 variants)
• Retinal atrophy;Central scotoma;Visual impairment;Macular degeneration (1 variants)
• Macular degeneration;Blindness;Visual loss (1 variants)
• Bietti crystalline corneoretinal dystrophy (1 variants)
• Severe early-childhood-onset retinal dystrophy;Cone-rod dystrophy 3 (1 variants)
• Visual impairment;Macular degeneration;Retinal atrophy;Central scotoma (1 variants)
• Age related macular degeneration 2;Retinitis pigmentosa 19;Severe early-childhood-onset retinal dystrophy;Cone-rod dystrophy 3 (1 variants)
• Severe early-childhood-onset retinal dystrophy;Cone-rod dystrophy 3;Retinitis pigmentosa 19 (1 variants)
• Cone-rod dystrophy 3;Retinitis pigmentosa 19;Age-related macular degeneration (1 variants)
• Age related macular degeneration 2;Cone-rod dystrophy 3;Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19 (1 variants)
• Severe early-childhood-onset retinal dystrophy;Age related macular degeneration 2;Retinitis pigmentosa 19;Cone-rod dystrophy 3 (1 variants)
• - (1 variants)
• Cone-rod dystrophy 3;Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19;Age related macular degeneration 2 (1 variants)
• Cone-rod dystrophy 3;Age related macular degeneration 2;Retinitis pigmentosa 19;Severe early-childhood-onset retinal dystrophy (1 variants)
• Cone-rod dystrophy 3;Retinitis pigmentosa 19;Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy (1 variants)
• Cone-rod dystrophy 3;Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19 (1 variants)
• Severe early-childhood-onset retinal dystrophy;Retinitis pigmentosa 19;Cone-rod dystrophy 3 (1 variants)
• Retinitis pigmentosa 19;Age related macular degeneration 2;Severe early-childhood-onset retinal dystrophy;Cone-rod dystrophy 3 (1 variants)
• Age-related macular degeneration;Retinitis pigmentosa 19;Cone-rod dystrophy 3 (1 variants)
• Leber congenital amaurosis 14 (1 variants)
• Stargardt disease;Cone-rod dystrophy (1 variants)
• Cone-rod dystrophy 3;Retinitis pigmentosa 19;Severe early-childhood-onset retinal dystrophy;Age related macular degeneration 2 (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	1	16	369	18	405
missense	168	324	750	25	3	1270
nonsense	125	28	1			154
start loss	2	2				4
frameshift	182	39	1			222
inframe indel	10	4	12			26
splice donor/acceptor (+/-2bp)	78	57	3			138
splice region	10	14	74	66	6	170
non coding	11	7	31	279	172	500
Total	577	462	814	673	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 Disorders	Benign/Likely benign (May 08, 2021)
1-93992938-C-G		Retinitis Pigmentosa, Recessive • Macular degeneration • Cone-Rod Dystrophy, Recessive • Stargardt Disease, Recessive • ABCA4-Related Disorders	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-93992953-A-G		ABCA4-Related Disorders	Uncertain significance (Jan 13, 2018)
1-93992983-G-T		ABCA4-Related Disorders	Uncertain significance (Mar 30, 2018)
1-93993009-T-A		ABCA4-Related Disorders	Uncertain significance (Jan 12, 2018)
1-93993090-G-A		Retinitis Pigmentosa, Recessive • Macular degeneration • Stargardt Disease, Recessive • Cone-Rod Dystrophy, Recessive • ABCA4-Related Disorders	Uncertain significance (Jan 12, 2018)
1-93993101-C-T		Macular degeneration • Stargardt Disease, Recessive • Cone-Rod Dystrophy, Recessive • Retinitis Pigmentosa, Recessive • ABCA4-Related Disorders	Conflicting classifications of pathogenicity (Jan 12, 2018)
1-93993103-C-T		Stargardt Disease, Recessive • Cone-Rod Dystrophy, Recessive • Macular degeneration • Retinitis Pigmentosa, Recessive • ABCA4-Related Disorders	Benign/Likely benign (Jul 05, 2018)
1-93993182-C-A		Cone-Rod Dystrophy, Recessive • Retinitis Pigmentosa, Recessive • Macular degeneration • Stargardt Disease, Recessive • ABCA4-Related Disorders	Likely benign (Apr 27, 2017)
1-93993211-G-T		Macular degeneration • Stargardt Disease, Recessive • Cone-Rod Dystrophy, Recessive • Retinitis Pigmentosa, Recessive • ABCA4-Related Disorders	Likely benign (Apr 27, 2017)
1-93993214-G-A		ABCA4-Related Disorders	Uncertain significance (Jan 12, 2018)
1-93993227-G-T		ABCA4-Related Disorders • not specified	Uncertain significance (Jan 13, 2018)
1-93993239-A-T		Cone-rod dystrophy 3	Uncertain significance (-)
1-93993244-T-C		Retinal dystrophy • Severe early-childhood-onset retinal dystrophy	Pathogenic/Likely pathogenic (Mar 29, 2024)
1-93993244-T-G			Pathogenic (Oct 06, 2023)
1-93993251-G-A			Likely benign (Aug 23, 2023)
1-93993259-C-T			Likely benign (Mar 11, 2021)
1-93993260-A-G			Likely benign (Sep 11, 2023)
1-93993261-T-G			Likely benign (Nov 05, 2023)
1-93993327-G-A			Benign (Nov 22, 2018)
1-93993444-A-T			Benign (Jul 14, 2018)
1-93995982-G-A			Benign (Jul 05, 2018)
1-93996081-C-G		not specified	Benign (Mar 03, 2015)
1-93996098-A-T			Likely benign (Apr 26, 2023)
1-93996100-C-T			Likely benign (May 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ABCA4	protein_coding	protein_coding	ENST00000370225	50	128296

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.35e-48	0.00607	125508	0	240	125748	0.000955

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.658	1306	1.24e+3	1.05	0.0000746	14895
Missense in Polyphen		430	459.99	0.93481		5686
Synonymous	-1.57	542	497	1.09	0.0000319	4485
Loss of Function	2.37	89	117	0.763	0.00000624	1336

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00144	0.00144
Ashkenazi Jewish	0.000300	0.000298
East Asian	0.000925	0.000925
Finnish	0.000231	0.000231
European (Non-Finnish)	0.00106	0.00106
Middle Eastern	0.000925	0.000925
South Asian	0.00187	0.00186
Other	0.000507	0.000489

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

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

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

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