ID P_HUMAN Reviewed; 838 AA. AC Q04671; Q15211; Q15212; Q96EN1; Q9UMI5; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 21-MAR-2006, sequence version 2. DT 27-MAR-2024, entry version 218. DE RecName: Full=P protein; DE AltName: Full=Melanocyte-specific transporter protein; DE AltName: Full=Pink-eyed dilution protein homolog; GN Name=OCA2 {ECO:0000312|HGNC:HGNC:8101}; Synonyms=D15S12, P; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), AND VARIANT ASP-257. RX PubMed=8421497; DOI=10.1038/361072a0; RA Rinchik E.M., Bultman S.J., Horsthemke B., Lee S.-T., Strunk K.M., RA Spritz R.A., Avidano K.A., Jong M.T.C., Nicholls R.D.; RT "A gene for the mouse pink-eyed dilution locus and for human type II RT oculocutaneous albinism."; RL Nature 361:72-76(1993). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 3), FUNCTION, SUBCELLULAR RP LOCATION, AND VARIANTS TRP-305; GLN-419; PHE-440; ARG-615 AND THR-722. RX PubMed=7601462; DOI=10.1016/0888-7543(95)80220-g; RA Lee S.-T., Nicholls R.D., Jong M.T.C., Fukai K., Spritz R.A.; RT "Organization and sequence of the human P gene and identification of a new RT family of transport proteins."; RL Genomics 26:354-363(1995). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 288-419, AND DISEASE. RC TISSUE=Skin; RX PubMed=1509264; DOI=10.1126/science.257.5073.1121; RA Gardner J.M., Nakatsu Y., Gondo Y., Lee S., Lyon M.F., King R.A., RA Brilliant M.H.; RT "The mouse pink-eyed dilution gene: association with human Prader-Willi and RT Angelman syndromes."; RL Science 257:1121-1124(1992). RN [5] RP FUNCTION. RX PubMed=11310796; DOI=10.1034/j.1600-0749.2001.140203.x; RA Brilliant M.H.; RT "The mouse p (pink-eyed dilution) and human P genes, oculocutaneous RT albinism type 2 (OCA2), and melanosomal pH."; RL Pigment Cell Res. 14:86-93(2001). RN [6] RP POSSIBLE INVOLVEMENT IN SKIN COLOR VARIATION. RX PubMed=11601658; DOI=10.1034/j.1600-0749.2001.140508.x; RA Manga P., Orlow S.J.; RT "Inverse correlation between pink-eyed dilution protein expression and RT induction of melanogenesis by bafilomycin A1."; RL Pigment Cell Res. 14:362-367(2001). RN [7] RP FUNCTION. RX PubMed=15262401; DOI=10.1016/j.tig.2004.06.010; RA Sturm R.A., Frudakis T.N.; RT "Eye colour: portals into pigmentation genes and ancestry."; RL Trends Genet. 20:327-332(2004). RN [8] RP REVIEW ON OCA2 VARIANTS. RX PubMed=10094567; RX DOI=10.1002/(sici)1098-1004(1999)13:2<99::aid-humu2>3.0.co;2-c; RA Oetting W.S., King R.A.; RT "Molecular basis of albinism: mutations and polymorphisms of pigmentation RT genes associated with albinism."; RL Hum. Mutat. 13:99-115(1999). RN [9] RP FUNCTION, AND INDUCTION. RX PubMed=22234890; DOI=10.1101/gr.128652.111; RA Visser M., Kayser M., Palstra R.J.; RT "HERC2 rs12913832 modulates human pigmentation by attenuating chromatin- RT loop formation between a long-range enhancer and the OCA2 promoter."; RL Genome Res. 22:446-455(2012). RN [10] RP FUNCTION, DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY. RX PubMed=32966160; DOI=10.1091/mbc.e20-03-0200; RA Le L., Escobar I.E., Ho T., Lefkovith A.J., Latteri E., RA Haltaufderhyde K.D., Dennis M.K., Plowright L., Sviderskaya E.V., RA Bennett D.C., Oancea E., Marks M.S.; RT "SLC45A2 protein stability and regulation of melanosome pH determine RT melanocyte pigmentation."; RL Mol. Biol. Cell 31:2687-2702(2020). RN [11] RP VARIANTS OCA2. RX PubMed=7874125; RA Lee S.-T., Nicholls R.D., Schnur R.E., Guida L.C., Lu-Kuo J., Spinner N.B., RA Zackai E.H., Spritz R.A.; RT "Diverse mutations of the P gene among African-Americans with type II RT (tyrosinase-positive) oculocutaneous albinism (OCA2)."; RL Hum. Mol. Genet. 3:2047-2051(1994). RN [12] RP VARIANTS OCA2. RX PubMed=7762554; RA Spritz R.A., Fukai K., Holmes S.A., Luande J.; RT "Frequent intragenic deletion of the P gene in Tanzanian patients with type RT II oculocutaneous albinism (OCA2)."; RL Am. J. Hum. Genet. 56:1320-1323(1995). RN [13] RP VARIANTS OCA2. RX PubMed=9259203; RX DOI=10.1002/(sici)1098-1004(1997)10:2<175::aid-humu12>3.0.co;2-x; RA Spritz R.A., Lee S.-T., Fukai K., Brondum-Nielsen K., Chitayat D., RA Lipson M.H., Musarella M.A., Rosenmann A., Weleber R.G.; RT "Novel mutations of the P gene in type II oculocutaneous albinism (OCA2)."; RL Hum. Mutat. 10:175-177(1997). RN [14] RP VARIANTS OCA2 ARG-86; PHE-112; VAL-368; ILE-592; PRO-724 AND VAL-787, AND RP VARIANT ASP-257. RX PubMed=10671067; RA Oetting W.S., Gardner J.M., Fryer J.P., Ching A., Durham-Pierre D., RA King R.A., Brilliant M.H.; RT "Mutations of the human P gene associated with type II oculocutaneous RT albinism (OCA2)."; RL Hum. Mutat. 12:434-434(1998). RN [15] RP VARIANTS OCA2 GLY-290; ILE-443; GLU-614; LEU-617; CYS-679; CYS-720; ARG-795 RP AND VAL-833 DEL, AND VARIANTS TRP-305 AND GLN-419. RX PubMed=10987646; DOI=10.1007/s004390051090; RA Passmore L.A., Kaesmann-Kellner B., Weber B.H.F.; RT "Novel and recurrent mutations in the tyrosinase gene and the P gene in the RT German albino population."; RL Hum. Genet. 105:200-210(1999). RN [16] RP VARIANT OCA2 VAL-334, AND VARIANTS UNCLASSIFIED OCA MET-350; THR-370; RP LYS-678; PHE-688 AND LEU-743. RX PubMed=10649493; RX DOI=10.1002/(sici)1098-1004(200002)15:2<166::aid-humu5>3.0.co;2-z; RA Kerr R., Stevens G., Manga P., Salm S., John P., Haw T., Ramsay M.; RT "Identification of P gene mutations in individuals with oculocutaneous RT albinism in sub-Saharan Africa."; RL Hum. Mutat. 15:166-172(2000). RN [17] RP VARIANTS TRP-305 AND GLN-419, AND INVOLVEMENT IN DETERMINATION OF EYE RP COLOR. RX PubMed=12163334; RA Rebbeck T.R., Kanetsky P.A., Walker A.H., Holmes R., Halpern A.C., RA Schuchter L.M., Elder D.E., Guerry D.; RT "P gene as an inherited biomarker of human eye color."; RL Cancer Epidemiol. Biomarkers Prev. 11:782-784(2002). RN [18] RP VARIANTS OCA2 GLY-290; ILE-443; ASP-489; CYS-679 AND LEU-743. RX PubMed=12876664; DOI=10.1086/377569; RA King R.A., Willaert R.K., Schmidt R.M., Pietsch J., Savage S., Brott M.J., RA Fryer J.P., Summers C.G., Oetting W.S.; RT "MC1R mutations modify the classic phenotype of oculocutaneous albinism RT type 2 (OCA2)."; RL Am. J. Hum. Genet. 73:638-645(2003). RN [19] RP VARIANTS OCA2 THR-481 AND HIS-799. RX PubMed=12727022; DOI=10.1016/s0923-1811(03)00005-7; RA Kato A., Fukai K., Oiso N., Hosomi N., Saitoh S., Wada T., Shimizu H., RA Ishii M.; RT "A novel P gene missense mutation in a Japanese patient with oculocutaneous RT albinism type II (OCA2)."; RL J. Dermatol. Sci. 31:189-192(2003). RN [20] RP VARIANTS OCA2 TRP-10; LEU-198; LEU-211; ILE-394 AND THR-481, AND VARIANTS RP MET-387 AND ARG-615. RX PubMed=12713581; DOI=10.1046/j.1523-1747.2003.12127.x; RA Suzuki T., Miyamura Y., Matsunaga J., Shimizu H., Kawachi Y., Ohyama N., RA Ishikawa O., Ishikawa T., Terao H., Tomita Y.; RT "Six novel P gene mutations and oculocutaneous albinism type 2 frequency in RT Japanese albino patients."; RL J. Invest. Dermatol. 120:781-783(2003). RN [21] RP VARIANTS TRP-305 AND GLN-419, AND INVOLVEMENT IN SUSCEPTIBILITY TO RP MELANOMA. RX PubMed=15889046; DOI=10.1038/sj.ejhg.5201415; RG Melan-Cohort; RA Jannot A.-S., Meziani R., Bertrand G., Gerard B., Descamps V., RA Archimbaud A., Picard C., Ollivaud L., Basset-Seguin N., Kerob D., RA Lanternier G., Lebbe C., Saiag P., Crickx B., Clerget-Darpoux F., RA Grandchamp B., Soufir N.; RT "Allele variations in the OCA2 gene (pink-eyed-dilution locus) are RT associated with genetic susceptibility to melanoma."; RL Eur. J. Hum. Genet. 13:913-920(2005). RN [22] RP INVOLVEMENT IN SHEP1, AND POLYMORPHISM. RX PubMed=17236130; DOI=10.1086/510885; RA Duffy D.L., Montgomery G.W., Chen W., Zhao Z.Z., Le L., James M.R., RA Hayward N.K., Martin N.G., Sturm R.A.; RT "A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 RT explains most human eye-color variation."; RL Am. J. Hum. Genet. 80:241-252(2007). RN [23] RP VARIANT [LARGE SCALE ANALYSIS] THR-773. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [24] RP INVOLVEMENT IN SHEP1, AND POLYMORPHISM. RX PubMed=17952075; DOI=10.1038/ng.2007.13; RA Sulem P., Gudbjartsson D.F., Stacey S.N., Helgason A., Rafnar T., RA Magnusson K.P., Manolescu A., Karason A., Palsson A., Thorleifsson G., RA Jakobsdottir M., Steinberg S., Palsson S., Jonasson F., Sigurgeirsson B., RA Thorisdottir K., Ragnarsson R., Benediktsdottir K.R., Aben K.K., RA Kiemeney L.A., Olafsson J.H., Gulcher J., Kong A., Thorsteinsdottir U., RA Stefansson K.; RT "Genetic determinants of hair, eye and skin pigmentation in Europeans."; RL Nat. Genet. 39:1443-1452(2007). RN [25] RP VARIANTS OCA2 ILE-443; ASP-476; ARG-775 AND HIS-827. RX PubMed=17385796; DOI=10.1002/pd.1713; RA Hongyi L., Haiyun W., Hui Z., Qing W., Honglei D., Shu M., Weiying J.; RT "Prenatal diagnosis of oculocutaneous albinism type II and novel mutations RT in two Chinese families."; RL Prenat. Diagn. 27:502-506(2007). RN [26] RP INVOLVEMENT IN SHEP1, AND POLYMORPHISM. RX PubMed=18252221; DOI=10.1016/j.ajhg.2007.10.003; RA Kayser M., Liu F., Janssens A.C.J.W., Rivadeneira F., Lao O., van Duijn K., RA Vermeulen M., Arp P., Jhamai M.M., van Ijcken W.F.J., den Dunnen J.T., RA Heath S., Zelenika D., Despriet D.D.G., Klaver C.C.W., Vingerling J.R., RA de Jong P.T.V.M., Hofman A., Aulchenko Y.S., Uitterlinden A.G., RA Oostra B.A., van Duijn C.M.; RT "Three genome-wide association studies and a linkage analysis identify RT HERC2 as a human iris color gene."; RL Am. J. Hum. Genet. 82:411-423(2008). RN [27] RP VARIANT GLN-419, FUNCTION, INDUCTION, INVOLVEMENT IN SHEP1, INVOLVEMENT IN RP SUSCEPTIBILITY TO MELANOMA, AND POLYMORPHISM. RX PubMed=18252222; DOI=10.1016/j.ajhg.2007.11.005; RA Sturm R.A., Duffy D.L., Zhao Z.Z., Leite F.P.M., Stark M.S., Hayward N.K., RA Martin N.G., Montgomery G.W.; RT "A single SNP in an evolutionary conserved region within intron 86 of the RT HERC2 gene determines human blue-brown eye color."; RL Am. J. Hum. Genet. 82:424-431(2008). RN [28] RP INVOLVEMENT IN SHEP1, POLYMORPHISM, AND INDUCTION. RX PubMed=18172690; DOI=10.1007/s00439-007-0460-x; RA Eiberg H., Troelsen J., Nielsen M., Mikkelsen A., Mengel-From J., RA Kjaer K.W., Hansen L.; RT "Blue eye color in humans may be caused by a perfectly associated founder RT mutation in a regulatory element located within the HERC2 gene inhibiting RT OCA2 expression."; RL Hum. Genet. 123:177-187(2008). RN [29] RP VARIANTS OCA2 MET-404; TRP-419; ILE-633; CYS-679 AND CYS-684. RX PubMed=23504663; DOI=10.1002/humu.22315; RA Simeonov D.R., Wang X., Wang C., Sergeev Y., Dolinska M., Bower M., RA Fischer R., Winer D., Dubrovsky G., Balog J.Z., Huizing M., Hart R., RA Zein W.M., Gahl W.A., Brooks B.P., Adams D.R.; RT "DNA variations in oculocutaneous albinism: an updated mutation list and RT current outstanding issues in molecular diagnostics."; RL Hum. Mutat. 34:827-835(2013). RN [30] RP FUNCTION, CHANNEL ACTIVITY, CHARACTERIZATION OF VARIANTS OCA2 ILE-443 AND RP GLU-614, AND SUBCELLULAR LOCATION. RX PubMed=25513726; DOI=10.7554/elife.04543; RA Bellono N.W., Escobar I.E., Lefkovith A.J., Marks M.S., Oancea E.; RT "An intracellular anion channel critical for pigmentation."; RL Elife 3:e04543-e04543(2014). CC -!- FUNCTION: Contributes to a melanosome-specific anion (chloride) current CC that modulates melanosomal pH for optimal tyrosinase activity required CC for melanogenesis and the melanosome maturation (PubMed:25513726, CC PubMed:11310796, PubMed:15262401, PubMed:22234890). One of the CC components of the mammalian pigmentary system (PubMed:15262401, CC PubMed:18252222, PubMed:7601462). May serve as a key control point at CC which ethnic skin color variation is determined. Major determinant of CC brown and/or blue eye color (PubMed:15262401, PubMed:18252222, CC PubMed:7601462). Seems to regulate the post-translational processing of CC tyrosinase, which catalyzes the limiting reaction in melanin synthesis CC (By similarity). {ECO:0000250|UniProtKB:Q62052, CC ECO:0000269|PubMed:11310796, ECO:0000269|PubMed:15262401, CC ECO:0000269|PubMed:18252222, ECO:0000269|PubMed:22234890, CC ECO:0000269|PubMed:25513726, ECO:0000269|PubMed:7601462}. CC -!- CATALYTIC ACTIVITY: CC Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823, CC ChEBI:CHEBI:17996; Evidence={ECO:0000305|PubMed:25513726}; CC -!- SUBCELLULAR LOCATION: Melanosome membrane {ECO:0000269|PubMed:25513726, CC ECO:0000269|PubMed:7601462}; Multi-pass membrane protein CC {ECO:0000269|PubMed:7601462}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q04671-1; Sequence=Displayed; CC Name=2; CC IsoId=Q04671-2; Sequence=VSP_012284; CC Name=3; CC IsoId=Q04671-3; Sequence=VSP_012285, VSP_012286; CC -!- TISSUE SPECIFICITY: Expressed in melanocytes and retinal pigment CC epithelium. {ECO:0000269|PubMed:25513726, ECO:0000269|PubMed:32966160}. CC -!- DEVELOPMENTAL STAGE: Expressed at early stages of melanosome CC differentiation. {ECO:0000269|PubMed:32966160}. CC -!- INDUCTION: Expression is under the control of an enhancer element that CC is encoded in an intron of the close-by HERC2 gene. The enhancer CC element containing the T-allele of the polymorphism rs12913832 mediates CC binding of the transcription factors HLTF, LEF1 and MITF and increases CC OCA2 expression. In contrast, transcription factor binding and OCA2 CC expression are reduced in carriers of the C-allele of polymorphism CC rs12913832. Thus, people homozygous for the C-allele have light-colored CC eyes, while people homozygous for the T-allele of polymorphism CC rs12913832 most often have brown eyes. {ECO:0000269|PubMed:18172690, CC ECO:0000269|PubMed:18252222, ECO:0000269|PubMed:22234890}. CC -!- POLYMORPHISM: Genetic variants in OCA2 define the skin/hair/eye CC pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as CC skin/hair/eye pigmentation type 1, blue/nonblue eyes or skin/hair/eye CC pigmentation type 1, blue/brown eyes or skin/hair/eye pigmentation type CC 1, blond/brown hair or eye color, brown/blue or eye color, blue/nonblue CC or eye color type 3 (EYCL3) or brown eye color type 2 (BEY2) or hair CC color type 3 (HCL3). Hair, eye and skin pigmentation are among the most CC visible examples of human phenotypic variation, with a broad normal CC range that is subject to substantial geographic stratification. In the CC case of skin, individuals tend to have lighter pigmentation with CC increasing distance from the equator. By contrast, the majority of CC variation in human eye and hair color is found among individuals of CC European ancestry, with most other human populations fixed for brown CC eyes and black hair. OCA2 polymorphisms may act as a penetrance CC modifier of the risk of malignant melanoma. CC {ECO:0000269|PubMed:17236130, ECO:0000269|PubMed:17952075, CC ECO:0000269|PubMed:18172690, ECO:0000269|PubMed:18252221, CC ECO:0000269|PubMed:18252222}. CC -!- DISEASE: Albinism, oculocutaneous, 2 (OCA2) [MIM:203200]: An autosomal CC recessive disorder in which the biosynthesis of melanin pigment is CC reduced in skin, hair, and eyes. Although affected infants may appear CC at birth to have complete absence of melanin pigment, most patients CC acquire small amounts of pigment with age. Visual anomalies include CC decreased acuity and nystagmus. The phenotype is highly variable. The CC hair of affected individuals may turn darker with age, and pigmented CC nevi or freckles may be seen. African and African American individuals CC may have yellow hair and blue-gray or hazel irides. One phenotypic CC variant, 'brown OCA,' has been described in African and African CC American populations and is characterized by light brown hair and skin CC color and gray to tan irides. {ECO:0000269|PubMed:10649493, CC ECO:0000269|PubMed:10671067, ECO:0000269|PubMed:10987646, CC ECO:0000269|PubMed:12713581, ECO:0000269|PubMed:12727022, CC ECO:0000269|PubMed:12876664, ECO:0000269|PubMed:17385796, CC ECO:0000269|PubMed:23504663, ECO:0000269|PubMed:25513726, CC ECO:0000269|PubMed:7762554, ECO:0000269|PubMed:7874125, CC ECO:0000269|PubMed:9259203}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the CitM (TC 2.A.11) transporter family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Mutations of the P gene; Note=Retina International's CC Scientific Newsletter; CC URL="https://www.retina-international.org/files/sci-news/pgenemut.htm"; CC -!- WEB RESOURCE: Name=Albinism database (ADB); Note=P mutations; CC URL="http://www.ifpcs.org/albinism/oca2mut.html"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Questioning colour - Issue CC 54 of January 2005; CC URL="https://web.expasy.org/spotlight/back_issues/054"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M99564; AAA36477.1; -; mRNA. DR EMBL; U19170; AAC13783.1; -; Genomic_DNA. DR EMBL; U19153; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19154; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19156; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19158; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19160; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19162; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19164; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19166; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19169; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19168; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19167; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19165; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19163; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19161; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19159; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19157; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19155; AAC13783.1; JOINED; Genomic_DNA. DR EMBL; U19176; AAC13784.1; -; Genomic_DNA. DR EMBL; U19153; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19154; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19155; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19157; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19158; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19159; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19160; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19161; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19162; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19163; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19164; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19165; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19166; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19167; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19168; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19169; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19171; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19172; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19173; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19174; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; U19175; AAC13784.1; JOINED; Genomic_DNA. DR EMBL; BC012097; AAH12097.1; -; mRNA. DR EMBL; M97901; AAA36430.1; -; mRNA. DR CCDS; CCDS10020.1; -. [Q04671-1] DR CCDS; CCDS73701.1; -. [Q04671-2] DR PIR; A57173; A57173. DR PIR; S28911; S28911. DR RefSeq; NP_000266.2; NM_000275.2. [Q04671-1] DR RefSeq; NP_001287913.1; NM_001300984.1. [Q04671-2] DR AlphaFoldDB; Q04671; -. DR BioGRID; 111002; 5. DR IntAct; Q04671; 3. DR STRING; 9606.ENSP00000346659; -. DR TCDB; 2.A.45.2.1; the arsenite-antimonite (arsb) efflux family. DR GlyCosmos; Q04671; 5 sites, No reported glycans. DR GlyGen; Q04671; 6 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q04671; -. DR PhosphoSitePlus; Q04671; -. DR BioMuta; OCA2; -. DR DMDM; 90110050; -. DR MassIVE; Q04671; -. DR PaxDb; 9606-ENSP00000346659; -. DR PeptideAtlas; Q04671; -. DR Antibodypedia; 22329; 206 antibodies from 25 providers. DR DNASU; 4948; -. DR Ensembl; ENST00000353809.9; ENSP00000261276.8; ENSG00000104044.16. [Q04671-2] DR Ensembl; ENST00000354638.8; ENSP00000346659.3; ENSG00000104044.16. [Q04671-1] DR GeneID; 4948; -. DR KEGG; hsa:4948; -. DR MANE-Select; ENST00000354638.8; ENSP00000346659.3; NM_000275.3; NP_000266.2. DR UCSC; uc001zbh.6; human. [Q04671-1] DR AGR; HGNC:8101; -. DR CTD; 4948; -. DR DisGeNET; 4948; -. DR GeneCards; OCA2; -. DR GeneReviews; OCA2; -. DR HGNC; HGNC:8101; OCA2. DR HPA; ENSG00000104044; Tissue enriched (choroid). DR MalaCards; OCA2; -. DR MIM; 203200; phenotype. DR MIM; 227220; phenotype. DR MIM; 611409; gene. DR neXtProt; NX_Q04671; -. DR OpenTargets; ENSG00000104044; -. DR Orphanet; 98794; Angelman syndrome due to maternal 15q11q13 deletion. DR Orphanet; 79432; Oculocutaneous albinism type 2. DR Orphanet; 98754; Prader-Willi syndrome due to maternal uniparental disomy of chromosome 15. DR Orphanet; 177901; Prader-Willi syndrome due to paternal deletion of 15q11q13 type 1. DR Orphanet; 177904; Prader-Willi syndrome due to paternal deletion of 15q11q13 type 2. DR PharmGKB; PA31890; -. DR VEuPathDB; HostDB:ENSG00000104044; -. DR eggNOG; KOG2639; Eukaryota. DR GeneTree; ENSGT01030000234550; -. DR HOGENOM; CLU_011920_2_1_1; -. DR InParanoid; Q04671; -. DR OMA; HHRIRDK; -. DR OrthoDB; 5481761at2759; -. DR PhylomeDB; Q04671; -. DR TreeFam; TF323556; -. DR PathwayCommons; Q04671; -. DR Reactome; R-HSA-5662702; Melanin biosynthesis. DR SignaLink; Q04671; -. DR SIGNOR; Q04671; -. DR BioGRID-ORCS; 4948; 8 hits in 1142 CRISPR screens. DR ChiTaRS; OCA2; human. DR GeneWiki; OCA2; -. DR GenomeRNAi; 4948; -. DR Pharos; Q04671; Tbio. DR PRO; PR:Q04671; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; Q04671; Protein. DR Bgee; ENSG00000104044; Expressed in pigmented layer of retina and 148 other cell types or tissues. DR ExpressionAtlas; Q04671; baseline and differential. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0033162; C:melanosome membrane; IDA:UniProtKB. DR GO; GO:0061778; F:intracellular chloride channel activity; IDA:UniProtKB. DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl. DR GO; GO:0035752; P:lysosomal lumen pH elevation; IDA:UniProtKB. DR GO; GO:0042438; P:melanin biosynthetic process; IBA:GO_Central. DR GO; GO:0006583; P:melanin biosynthetic process from tyrosine; IDA:UniProtKB. DR GO; GO:0030318; P:melanocyte differentiation; IBA:GO_Central. DR GO; GO:0007286; P:spermatid development; IEA:Ensembl. DR CDD; cd01116; P_permease; 1. DR InterPro; IPR004680; Cit_transptr-like_dom. DR PANTHER; PTHR43568; P PROTEIN; 1. DR PANTHER; PTHR43568:SF1; P PROTEIN; 1. DR Pfam; PF03600; CitMHS; 1. DR Genevisible; Q04671; HS. PE 1: Evidence at protein level; KW Albinism; Alternative splicing; Disease variant; Glycoprotein; Membrane; KW Reference proteome; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..838 FT /note="P protein" FT /id="PRO_0000172509" FT TOPO_DOM 1..179 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 180..197 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 198..330 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 331..347 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 348..353 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 354..370 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 371..384 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 385..401 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 402..423 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 424..440 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 441..513 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 514..530 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 531..620 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 621..637 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 638..647 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 648..664 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 665..679 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 680..696 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 697..720 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 721..737 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 738..760 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 761..777 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 778..817 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 818..834 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 835..838 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 38..60 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 74..94 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 214 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 218 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 273 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 442 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 781 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 349..372 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_012284" FT VAR_SEQ 652..668 FT /note="WIAILGAIWLLILADIH -> GLGLVQAGRYYLSTPES (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:8421497" FT /id="VSP_012285" FT VAR_SEQ 669..838 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8421497" FT /id="VSP_012286" FT VARIANT 10 FT /note="R -> W (in OCA2; dbSNP:rs554862186)" FT /evidence="ECO:0000269|PubMed:12713581" FT /id="VAR_020622" FT VARIANT 27 FT /note="G -> R (in OCA2; dbSNP:rs61738394)" FT /id="VAR_006117" FT VARIANT 86 FT /note="S -> R (in OCA2; dbSNP:rs772243109)" FT /evidence="ECO:0000269|PubMed:10671067" FT /id="VAR_006118" FT VARIANT 112 FT /note="C -> F (in OCA2; dbSNP:rs562649990)" FT /evidence="ECO:0000269|PubMed:10671067" FT /id="VAR_006119" FT VARIANT 198 FT /note="P -> L (in OCA2; dbSNP:rs183487020)" FT /evidence="ECO:0000269|PubMed:12713581" FT /id="VAR_020623" FT VARIANT 206..211 FT /note="Missing (in OCA2; severe)" FT /id="VAR_006120" FT VARIANT 211 FT /note="P -> L (in OCA2; dbSNP:rs190612616)" FT /evidence="ECO:0000269|PubMed:12713581" FT /id="VAR_020624" FT VARIANT 241 FT /note="P -> R (in dbSNP:rs2305253)" FT /id="VAR_022019" FT VARIANT 257 FT /note="A -> D (in dbSNP:rs1050968)" FT /evidence="ECO:0000269|PubMed:10671067, FT ECO:0000269|PubMed:8421497" FT /id="VAR_006121" FT VARIANT 266 FT /note="R -> W (in dbSNP:rs33929465)" FT /id="VAR_032094" FT VARIANT 273..274 FT /note="NW -> KV (in OCA2; dbSNP:rs797044784)" FT /id="VAR_006122" FT VARIANT 290 FT /note="R -> G (in OCA2; dbSNP:rs769408559)" FT /evidence="ECO:0000269|PubMed:10987646, FT ECO:0000269|PubMed:12876664" FT /id="VAR_020625" FT VARIANT 305 FT /note="R -> W (affects eye pigmentation and is correlated FT with non-blue eye color; dbSNP:rs1800401)" FT /evidence="ECO:0000269|PubMed:10987646, FT ECO:0000269|PubMed:12163334, ECO:0000269|PubMed:15889046, FT ECO:0000269|PubMed:7601462" FT /id="VAR_006123" FT VARIANT 334 FT /note="A -> V (in OCA2; dbSNP:rs121918168)" FT /evidence="ECO:0000269|PubMed:10649493" FT /id="VAR_020626" FT VARIANT 336 FT /note="A -> V (in dbSNP:rs34010619)" FT /id="VAR_032095" FT VARIANT 350 FT /note="V -> M (in unclassified OCA; dbSNP:rs533478642)" FT /evidence="ECO:0000269|PubMed:10649493" FT /id="VAR_020627" FT VARIANT 368 FT /note="A -> V (in OCA2; dbSNP:rs61745150)" FT /evidence="ECO:0000269|PubMed:10671067" FT /id="VAR_006124" FT VARIANT 370 FT /note="I -> T (in unclassified OCA; dbSNP:rs34731820)" FT /evidence="ECO:0000269|PubMed:10649493" FT /id="VAR_020628" FT VARIANT 385 FT /note="F -> I (in OCA2; severe; dbSNP:rs137956605)" FT /id="VAR_006125" FT VARIANT 387 FT /note="T -> M (in dbSNP:rs150335311)" FT /evidence="ECO:0000269|PubMed:12713581" FT /id="VAR_020629" FT VARIANT 394 FT /note="M -> I (in OCA2; dbSNP:rs121918171)" FT /evidence="ECO:0000269|PubMed:12713581" FT /id="VAR_020630" FT VARIANT 395 FT /note="M -> L (in OCA2; severe; dbSNP:rs757286784)" FT /id="VAR_006126" FT VARIANT 404 FT /note="T -> M (in OCA2; dbSNP:rs144812594)" FT /evidence="ECO:0000269|PubMed:23504663" FT /id="VAR_006127" FT VARIANT 419 FT /note="R -> Q (affects eye pigmentation and is correlated FT with green/hazel eye color; dbSNP:rs1800407)" FT /evidence="ECO:0000269|PubMed:10987646, FT ECO:0000269|PubMed:12163334, ECO:0000269|PubMed:15889046, FT ECO:0000269|PubMed:18252222, ECO:0000269|PubMed:7601462" FT /id="VAR_006128" FT VARIANT 419 FT /note="R -> W (in OCA2; dbSNP:rs143218168)" FT /evidence="ECO:0000269|PubMed:23504663" FT /id="VAR_006129" FT VARIANT 425 FT /note="Missing (in OCA2; mild; dbSNP:rs752510351)" FT /id="VAR_006130" FT VARIANT 440 FT /note="L -> F (in dbSNP:rs1800408)" FT /evidence="ECO:0000269|PubMed:7601462" FT /id="VAR_007939" FT VARIANT 440 FT /note="L -> H" FT /id="VAR_006131" FT VARIANT 443 FT /note="V -> I (in OCA2; reduced flow of chloride ions; no FT effect on subcellular location; slightly increased luminal FT pH; dbSNP:rs121918166)" FT /evidence="ECO:0000269|PubMed:10987646, FT ECO:0000269|PubMed:12876664, ECO:0000269|PubMed:17385796, FT ECO:0000269|PubMed:25513726" FT /id="VAR_006132" FT VARIANT 446 FT /note="M -> V (in OCA2; mild; AROA form; FT dbSNP:rs140566426)" FT /id="VAR_006133" FT VARIANT 473 FT /note="I -> S (in OCA2)" FT /id="VAR_006134" FT VARIANT 476 FT /note="N -> D (in OCA2)" FT /evidence="ECO:0000269|PubMed:17385796" FT /id="VAR_043700" FT VARIANT 481 FT /note="A -> T (in OCA2; dbSNP:rs74653330)" FT /evidence="ECO:0000269|PubMed:12713581, FT ECO:0000269|PubMed:12727022" FT /id="VAR_007940" FT VARIANT 489 FT /note="N -> D (in OCA2; mild/severe; dbSNP:rs121918170)" FT /evidence="ECO:0000269|PubMed:12876664" FT /id="VAR_006135" FT VARIANT 519 FT /note="V -> A (in dbSNP:rs41446944)" FT /id="VAR_032096" FT VARIANT 549 FT /note="H -> Q (in OCA2)" FT /id="VAR_006136" FT VARIANT 560 FT /note="R -> H (in dbSNP:rs35110389)" FT /id="VAR_032097" FT VARIANT 592 FT /note="T -> I (in OCA2; dbSNP:rs1800413)" FT /evidence="ECO:0000269|PubMed:10671067" FT /id="VAR_006137" FT VARIANT 614 FT /note="K -> E (in OCA2; no effect on flow of chloride ions; FT no effect on subcellular location; no effect on luminal FT pH)" FT /evidence="ECO:0000269|PubMed:10987646, FT ECO:0000269|PubMed:25513726" FT /id="VAR_020631" FT VARIANT 614 FT /note="K -> N (in OCA2)" FT /id="VAR_006138" FT VARIANT 615 FT /note="H -> R (in dbSNP:rs1800414)" FT /evidence="ECO:0000269|PubMed:12713581, FT ECO:0000269|PubMed:7601462" FT /id="VAR_006139" FT VARIANT 617 FT /note="I -> L (in OCA2; dbSNP:rs763016773)" FT /evidence="ECO:0000269|PubMed:10987646" FT /id="VAR_020632" FT VARIANT 633 FT /note="V -> I (in OCA2; dbSNP:rs1372200062)" FT /evidence="ECO:0000269|PubMed:23504663" FT /id="VAR_072600" FT VARIANT 652 FT /note="W -> R (in OCA2; dbSNP:rs886043514)" FT /id="VAR_006140" FT VARIANT 678 FT /note="E -> K (in unclassified OCA)" FT /evidence="ECO:0000269|PubMed:10649493" FT /id="VAR_020633" FT VARIANT 679 FT /note="W -> C (in OCA2; dbSNP:rs121918169)" FT /evidence="ECO:0000269|PubMed:10987646, FT ECO:0000269|PubMed:12876664, ECO:0000269|PubMed:23504663" FT /id="VAR_020634" FT VARIANT 679 FT /note="W -> R (in OCA2; severe; dbSNP:rs751822606)" FT /id="VAR_006141" FT VARIANT 684 FT /note="F -> C (in OCA2; dbSNP:rs772754008)" FT /evidence="ECO:0000269|PubMed:23504663" FT /id="VAR_072601" FT VARIANT 688 FT /note="L -> F (in unclassified OCA)" FT /evidence="ECO:0000269|PubMed:10649493" FT /id="VAR_020635" FT VARIANT 720 FT /note="R -> C (in OCA2; dbSNP:rs141545475)" FT /evidence="ECO:0000269|PubMed:10987646" FT /id="VAR_020636" FT VARIANT 722 FT /note="I -> T (in dbSNP:rs1800417)" FT /evidence="ECO:0000269|PubMed:7601462" FT /id="VAR_006142" FT VARIANT 724 FT /note="A -> P (in OCA2)" FT /evidence="ECO:0000269|PubMed:10671067" FT /id="VAR_006143" FT VARIANT 736 FT /note="S -> L (in OCA2; dbSNP:rs780296175)" FT /id="VAR_006144" FT VARIANT 743 FT /note="P -> L (in OCA2 and unclassified OCA; FT dbSNP:rs121918167)" FT /evidence="ECO:0000269|PubMed:10649493, FT ECO:0000269|PubMed:12876664" FT /id="VAR_006145" FT VARIANT 773 FT /note="A -> T (in a breast cancer sample; somatic mutation; FT dbSNP:rs1184589806)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036468" FT VARIANT 775 FT /note="G -> R (in OCA2)" FT /evidence="ECO:0000269|PubMed:17385796" FT /id="VAR_043701" FT VARIANT 787 FT /note="A -> V (in OCA2; dbSNP:rs200457227)" FT /evidence="ECO:0000269|PubMed:10671067" FT /id="VAR_006146" FT VARIANT 795 FT /note="G -> R (in OCA2)" FT /evidence="ECO:0000269|PubMed:10987646" FT /id="VAR_020637" FT VARIANT 799 FT /note="Q -> H (in OCA2)" FT /evidence="ECO:0000269|PubMed:12727022" FT /id="VAR_020638" FT VARIANT 827 FT /note="Y -> H (in OCA2; dbSNP:rs1255943449)" FT /evidence="ECO:0000269|PubMed:17385796" FT /id="VAR_043702" FT VARIANT 833 FT /note="Missing (in OCA2; dbSNP:rs751440917)" FT /evidence="ECO:0000269|PubMed:10987646" FT /id="VAR_021682" SQ SEQUENCE 838 AA; 92850 MW; A6158B9E55BD7199 CRC64; MHLEGRDGRR YPGAPAVELL QTSVPSGLAE LVAGKRRLPR GAGGADPSHS CPRGAAGQSS WAPAGQEFAS FLTKGRSHSS LPQMSSSRSK DSCFTENTPL LRNSLQEKGS RCIPVYHPEF ITAEESWEDS SADWERRYLL SREVSGLSAS ASSEKGDLLD SPHIRLRLSK LRRCVQWLKV MGLFAFVVLC SILFSLYPDQ GKLWQLLALS PLENYSVNLS SHVDSTLLQV DLAGALVASG PSRPGREEHI VVELTQADAL GSRWRRPQQV THNWTVYLNP RRSEHSVMSR TFEVLTRETV SISIRASLQQ TQAVPLLMAH QYLRGSVETQ VTIATAILAG VYALIIFEIV HRTLAAMLGS LAALAALAVI GDRPSLTHVV EWIDFETLAL LFGMMILVAI FSETGFFDYC AVKAYRLSRG RVWAMIIMLC LIAAVLSAFL DNVTTMLLFT PVTIRLCEVL NLDPRQVLIA EVIFTNIGGA ATAIGDPPNV IIVSNQELRK MGLDFAGFTA HMFIGICLVL LVCFPLLRLL YWNRKLYNKE PSEIVELKHE IHVWRLTAQR ISPASREETA VRRLLLGKVL ALEHLLARRL HTFHRQISQE DKNWETNIQE LQKKHRISDG ILLAKCLTVL GFVIFMFFLN SFVPGIHLDL GWIAILGAIW LLILADIHDF EIILHRVEWA TLLFFAALFV LMEALAHLHL IEYVGEQTAL LIKMVPEEQR LIAAIVLVVW VSALASSLID NIPFTATMIP VLLNLSHDPE VGLPAPPLMY ALAFGACLGG NGTLIGASAN VVCAGIAEQH GYGFSFMEFF RLGFPMMVVS CTVGMCYLLV AHVVVGWN //