OCA2

Summary

OCA2 (OCA2 melanosomal transmembrane protein, HGNC:8101) is a protein-coding gene on chromosome 15q12-q13.1, encoding P protein (Q04671). Contributes to a melanosome-specific anion (chloride) current that modulates melanosomal pH for optimal tyrosinase activity required for melanogenesis and the melanosome maturation.

This gene encodes the human homolog of the mouse p (pink-eyed dilution) gene. The encoded protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine, which is a precursor to melanin synthesis. It is involved in mammalian pigmentation, where it may control skin color variation and act as a determinant of brown or blue eye color. Mutations in this gene result in type 2 oculocutaneous albinism. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4948 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oculocutaneous albinism type 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 83
• Clinical variants (ClinVar): 1,505 total — 179 pathogenic, 122 likely-pathogenic
• Phenotypes (HPO): 142
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000275

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8101
Approved symbol	OCA2
Name	OCA2 melanosomal transmembrane protein
Location	15q12-q13.1
Locus type	gene with protein product
Status	Approved
Aliases	BEY, BEY1, BEY2, EYCL, SLC13B1
Ensembl gene	ENSG00000104044
Ensembl biotype	protein_coding
OMIM	611409
Entrez	4948

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000353809, ENST00000354638, ENST00000431101, ENST00000445578, ENST00000910119, ENST00000910120, ENST00000943939, ENST00000943940, ENST00000943941, ENST00000943942

RefSeq mRNA: 2 — MANE Select: NM_000275 NM_000275, NM_001300984

CCDS: CCDS10020, CCDS73701

Canonical transcript exons

ENST00000354638 — 24 exons

Exon	Start	End
ENSE00000672758	27926127	27926254
ENSE00000672773	27985064	27985188
ENSE00000672775	27986587	27986643
ENSE00000672778	27989601	27989666
ENSE00000672781	27990576	27990647
ENSE00000672784	28014776	28014929
ENSE00000672786	28018397	28018557
ENSE00000672787	28022501	28022573
ENSE00000672788	28024845	28024902
ENSE00000672789	28027871	28028059
ENSE00000897447	27844959	27845052
ENSE00000897458	27851382	27851475
ENSE00000897468	27871154	27871258
ENSE00000897479	27871863	27871922
ENSE00001001825	27955158	27955215
ENSE00001001826	27951784	27951892
ENSE00001127194	27754875	27755472
ENSE00001145122	27957588	27957735
ENSE00001145127	27966690	27966822
ENSE00001145133	27983345	27983483
ENSE00001223735	28032065	28032163
ENSE00001223762	28081648	28081895
ENSE00001894523	28099224	28099315
ENSE00003789046	28016104	28016186

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 91.27.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6948 / max 407.9867, expressed in 162 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149049	1.6572	160
149048	0.0376	13

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	91.27	gold quality
choroid plexus epithelium	UBERON:0003911	90.54	gold quality
secondary oocyte	CL:0000655	90.32	gold quality
type B pancreatic cell	CL:0000169	90.00	gold quality
olfactory bulb	UBERON:0002264	89.72	gold quality
oocyte	CL:0000023	89.22	gold quality
hair follicle	UBERON:0002073	88.48	gold quality
cervix squamous epithelium	UBERON:0006922	86.48	gold quality
cervix epithelium	UBERON:0004801	84.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.74	gold quality
male germ cell	CL:0000015	81.38	silver quality
cortical plate	UBERON:0005343	81.06	gold quality
epithelium of nasopharynx	UBERON:0001951	80.90	silver quality
mucosa of urinary bladder	UBERON:0001259	80.60	gold quality
sperm	CL:0000019	80.39	silver quality
upper arm skin	UBERON:0004263	80.23	silver quality
mammalian vulva	UBERON:0000997	77.93	gold quality
epithelial cell of pancreas	CL:0000083	77.92	gold quality
thymus	UBERON:0002370	77.87	gold quality
penis	UBERON:0000989	77.67	gold quality
squamous epithelium	UBERON:0006914	77.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.28	gold quality
epithelium of esophagus	UBERON:0001976	77.08	gold quality
esophagus squamous epithelium	UBERON:0006920	76.58	gold quality
nipple	UBERON:0002030	76.45	silver quality
cardia of stomach	UBERON:0001162	75.76	gold quality
popliteal artery	UBERON:0002250	75.57	gold quality
vena cava	UBERON:0004087	75.55	gold quality
tibial artery	UBERON:0007610	75.55	gold quality
dorsal plus ventral thalamus	UBERON:0001897	75.40	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	6434.24
E-GEOD-81383	yes	351.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, HLTF, LEF1, MITF, MYC, PITX2, TBX2

miRNA regulators (miRDB)

36 targeting OCA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4711-3P	98.97	66.87	1020
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-561-5P	98.25	68.13	1365

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• role of P protein and tyrosinase in oculocutaneous albinism (PMID:12028586)
• P gene, in part, determiontes normal phenotypic variation in human eye color and may represent an inherited biomarkers of cutaneous cancer risk (PMID:12163334)
• A 122.5-kilobase deletion of the P gene underlies the high prevalence of oculocutaneous albinism type 2 in the Navajo population (PMID:12469324)
• We show that OCA2 has measurable effects on skin pigmentation differences between the west African and west European parental populations. (PMID:12579416)
• two missense substitutions, A481T and Q799H in the P gene in oculocutaneous albinism (PMID:12727022)
• A candidate gene for pigmentation. (PMID:12817591)
• 9 novel mutations and 12 novel polymorphisms associated with oculocutaneous albinism type II are reported. (PMID:15712365)
• we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). (PMID:15889046)
• The macular hypoplasia has to be considered a concerted interaction with compound heterozygous mutations in the P gene manifesting a mild form of oculocutaneous albinism. (PMID:16453125)
• Differences within the 5’ proximal regulatory control region of the OCA2 gene alter expression or messenger RNA-transcript levels and may be responsible for eye-color and other pigmentary trait associations. (PMID:17236130)
• These findings suggest that OCA2 481Thr arose in a region of low ultraviolet radiation and thereafter spread to neighboring populations. (PMID:17568986)
• results confirm that OCA2 is the major human iris color gene and suggest that using an empirical database-driven system, genotypes from a modest number of SNPs within this gene can be used to accurately predict iris melanin content from DNA (PMID:17619204)
• 3 different haplotypes (TAGCT, TAGTT and TAGCC with frequencies of 0.66, 0.28 and 0.06, respectively) associated with the mutation in the 53 OCA2 patients, while 11 different haplotypes were observed in the control group (PMID:17767372)
• Pink-eye-dilution gene mutations underlie oculocutaneous albinism in this family. Two known mutations in MC1R caused red hair color in one family member. No modifier effect of MC1R on P mutations could be deduced. (PMID:17960121)
• Variation present in the OCA2 gene and perhaps some other pigment related genes must be taken into account in order to explain the high phenotypic variation in iris colour. (PMID:18093281)
• Most patients with AROA (autosomal recessive ocular albinism) represent phenotypically mild variants of oculocutaneous albinism , well over half of which is OCA1. (PMID:18326704)
• OCA2 and HERC2 have roles in hair color in Australian adolescents (PMID:18528436)
• strong correlations in MATP-L374F, OCA2, and melanocortin-1 receptor with skin, eye, and hair color variation, respectively (PMID:18650849)
• Oculocutaneous albinism phenotype (OCA2) can be modified by mutation in TYRP1. (PMID:18680187)
• TYR is the major OCA (oculocutaneous albinism) gene in Denmark, but several patients do not have mutations in the investigated genes. (PMID:19060277)
• OCA2 is targeted to and functions within melanosomes but that residence within melanosomes may be regulated by secondary or alternative targeting to lysosomes. (PMID:19116314)
• It is concluded that OCA2 rs1800407 is associated with eye colour. (PMID:19208107)
• The variant allele of OCA2 R419Q (rs1800407) is associated with increased risk of malignant melanoma. (PMID:19320733)
• Polymorphism of pigmentation genes (OCA2 and ASIP) in some populations of Russia (PMID:19382693)
• The OCA2 Arg419Gln is associated with basal cell carcinoma (PMID:19384953)
• Three single nucleotide polymorphisms found within intron 1 of the OCA2 gene (rs7495174, rs4778241, rs4778138). 30 UTR region (rs1129038) of the HERC2 gene (PMID:19472299)
• In 5 israeli families a P gene mutation was detected. (PMID:19626598)
• Inheritance of a novel mutated allele of the OCA2 gene associated with high incidence of oculocutaneous albinism in a Polynesian community. (PMID:20019752)
• The non-synonymous polymorphism rs1800414 (His615Arg) located within the OCA2 gene is significantly associated with skin pigmentation in this sample. (PMID:20221248)
• ). Sequence variations in rs11636232 and rs7170852 in HERC2, rs1800407 in OCA2 and rs16891982 in MATP showed additional association with eye colours (PMID:20457063)
• role in pigmentation characteristics in Spanish population (PMID:20629734)
• TYR gene mutations represent a relevant cause of oculocutaneous albinism in Italy, whereas mutations in P present a lower frequency. Clinical analysis revealed that the severity of the ocular manifestations depends on the degree of retinal pigmentation. (PMID:20861488)
• Using quantitative multiplex fluorescent PCR and very high-resolution array-CGH focussed on the OCA2 gene and surrounding regions in 15q12, study identified 2 new gene deletions and 1 duplication in Oculocutaneous albinism type 2 patients. (PMID:21085994)
• TYR gene mutations have a more severe effect on pigmentation than mutations in OCA2 and the GPR143 gene. Nevertheless, mutations in these genes affect the development of visual function either directly or by interaction with other genes like MC1R. (PMID:21541274)
• In this paper I shall discuss the anatomy and genetics of normal eye colour, together with a wide and diverse range of conditions that may produce an alteration in normal iris pigmentation or form. (PMID:21979861)
• Three mutational alleles, R278X and R52I of the TYR gene and C229Y of the SLC45A2 gene, are added to the mutational spectra of Korean patients with oculocutaneous albinism (OCA) (PMID:22042571)
• Although variants within OCA2 were tested for association, the 2.7kb deletion allele of OCA2 was not tested. This led us to hypothesize that the deletion allele may confer resistance to susceptibility (PMID:23063908)
• The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation and supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition. (PMID:23103111)
• We examined the association between 12 variants of four pigmentation-related genes (TYR, OCA2, SLC45A2, MC1R) and variations in the melanin index of 456 Japanese females using a multiple regression analysis. (PMID:23165166)
• given a particular HERC2/OCA2 genotype, males are more prone to have lighter eye colors than predicted by their genotypes, while females tend to have darker eye colors than predicted (PMID:23601698)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	oca2	ENSDARG00000061303
mus_musculus	Oca2	ENSMUSG00000030450
rattus_norvegicus	Oca2	ENSRNOG00000014465
drosophila_melanogaster	hoe2	FBGN0031649
drosophila_melanogaster	CG13801	FBGN0035332
drosophila_melanogaster	CG11262	FBGN0036329
drosophila_melanogaster	hoe1	FBGN0041150
drosophila_melanogaster	CG31693	FBGN0051693

Paralogs (5): SLC13A2 (ENSG00000007216), SLC13A1 (ENSG00000081800), SLC13A5 (ENSG00000141485), SLC13A3 (ENSG00000158296), SLC13A4 (ENSG00000164707)

Protein

Protein identifiers

P protein — Q04671 (reviewed: Q04671)

Alternative names: Melanocyte-specific transporter protein, Pink-eyed dilution protein homolog

All UniProt accessions (3): C9JDV3, C9JLG9, Q04671

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to a melanosome-specific anion (chloride) current that modulates melanosomal pH for optimal tyrosinase activity required for melanogenesis and the melanosome maturation. One of the components of the mammalian pigmentary system. May serve as a key control point at which ethnic skin color variation is determined. Major determinant of brown and/or blue eye color. Seems to regulate the post-translational processing of tyrosinase, which catalyzes the limiting reaction in melanin synthesis.

Subcellular location. Melanosome membrane.

Tissue specificity. Expressed in melanocytes and retinal pigment epithelium.

Disease relevance. Albinism, oculocutaneous, 2 (OCA2) [MIM:203200] An autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Although affected infants may appear at birth to have complete absence of melanin pigment, most patients acquire small amounts of pigment with age. Visual anomalies include decreased acuity and nystagmus. The phenotype is highly variable. The hair of affected individuals may turn darker with age, and pigmented nevi or freckles may be seen. African and African American individuals may have yellow hair and blue-gray or hazel irides. One phenotypic variant, ‘brown OCA,’ has been described in African and African American populations and is characterized by light brown hair and skin color and gray to tan irides. The disease is caused by variants affecting the gene represented in this entry.

Induction. Expression is under the control of an enhancer element that is encoded in an intron of the close-by HERC2 gene. The enhancer element containing the T-allele of the polymorphism rs12913832 mediates binding of the transcription factors HLTF, LEF1 and MITF and increases OCA2 expression. In contrast, transcription factor binding and OCA2 expression are reduced in carriers of the C-allele of polymorphism rs12913832. Thus, people homozygous for the C-allele have light-colored eyes, while people homozygous for the T-allele of polymorphism rs12913832 most often have brown eyes.

Polymorphism. Genetic variants in OCA2 define the skin/hair/eye pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as skin/hair/eye pigmentation type 1, blue/nonblue eyes or skin/hair/eye pigmentation type 1, blue/brown eyes or skin/hair/eye pigmentation type 1, blond/brown hair or eye color, brown/blue or eye color, blue/nonblue or eye color type 3 (EYCL3) or brown eye color type 2 (BEY2) or hair color type 3 (HCL3). Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair. OCA2 polymorphisms may act as a penetrance modifier of the risk of malignant melanoma.

Similarity. Belongs to the CitM (TC 2.A.11) transporter family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q04671-1	1	yes
Q04671-2	2
Q04671-3	3

RefSeq proteins (2): NP_000266, NP_001287913 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004680	Cit_transptr-like_dom	Domain
IPR051475	Diverse_Ion_Transporter	Family

Pfam: PF03600

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (98 total): sequence variant 61, topological domain 13, transmembrane region 12, glycosylation site 5, splice variant 3, region of interest 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04671-F1	73.79	0.27

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (5): 214, 218, 273, 442, 781

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5662702	Melanin biosynthesis

MSigDB gene sets: 424 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, chr15q13, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_MALE_GAMETE_GENERATION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_PIGMENTATION, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_CHLORIDE_TRANSPORT, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_14HR_DN

GO Biological Process (10): melanin biosynthetic process from tyrosine (GO:0006583), spermatid development (GO:0007286), cell population proliferation (GO:0008283), melanocyte differentiation (GO:0030318), lysosomal lumen pH elevation (GO:0035752), melanin biosynthetic process (GO:0042438), pigmentation (GO:0043473), developmental pigmentation (GO:0048066), transmembrane transport (GO:0055085), chloride transmembrane transport (GO:1902476)

GO Molecular Function (2): chloride channel activity (GO:0005254), protein binding (GO:0005515)

GO Cellular Component (5): lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), endosome membrane (GO:0010008), melanosome membrane (GO:0033162), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
melanin biosynthetic process	1
germ cell development	1
spermatid differentiation	1
pigment cell differentiation	1
intracellular pH elevation	1
melanin metabolic process	1
secondary metabolite biosynthetic process	1
pigment biosynthetic process	1
phenol-containing compound biosynthetic process	1
biological_process	1
pigmentation	1
transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
binding	1
lysosome	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
melanosome	1
chitosome	1
pigment granule membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2054 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OCA2	MYBPH	Q13203	996
OCA2	AMT	P48728	986
OCA2	TYR	P14679	984
OCA2	SLC45A2	Q9UMX9	976
OCA2	TYRP1	P17643	964
OCA2	SLC24A5	Q71RS6	946
OCA2	GCSH	P23434	943
OCA2	MC1R	Q01726	936
OCA2	GLDC	P23378	897
OCA2	GPR143	P51810	876
OCA2	SLC24A4	Q8NFF2	849
OCA2	STAT1	P42224	846
OCA2	ASIP	P42127	811
OCA2	MKRN3	Q13064	798
OCA2	HERC2	O95714	793

IntAct

6 interactions, top by confidence:

A	B	Type	Score
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
OCA2	ATP13A2	psi-mi:“MI:0915”(physical association)	0.370
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HTR3A	EXTL3	psi-mi:“MI:0914”(association)	0.350
OCA2	PSMD11	psi-mi:“MI:0914”(association)	0.350

BioGRID (72): OCA2 (Affinity Capture-MS), OCA2 (Affinity Capture-MS), OCA2 (Proximity Label-MS), OCA2 (Affinity Capture-MS), OCA2 (Affinity Capture-MS), OCA2 (Affinity Capture-MS), ACO2 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), AHCY (Affinity Capture-MS), ALDOA (Affinity Capture-MS), AP3D1 (Affinity Capture-MS), ATIC (Affinity Capture-MS), BRI3BP (Affinity Capture-MS), CALR (Affinity Capture-MS), CIR1 (Affinity Capture-MS)

ESM2 similar proteins: A1A5B4, A2AHL1, A2BIE7, A2RRU4, A5PK40, A6NDV4, A6QLK4, A6QM06, B1AWJ5, E9PTA2, E9Q6C8, O94759, P86044, P97260, Q04671, Q12770, Q17QL9, Q3TD49, Q49LS8, Q4R7X9, Q5F383, Q5GH57, Q5MNU5, Q5PQL3, Q5RBY7, Q5ZMP3, Q60HE8, Q6AY05, Q6GQT6, Q6UX01, Q7RTT9, Q7TN60, Q7Z403, Q8IU68, Q8MIQ9, Q8N4M1, Q8R139, Q8R4F0, Q8TCT7, Q91YD4

Diamond homologs: A5F6Z3, B7LSJ8, C3LNK5, P0A607, P46838, P74635, P9WPD6, P9WPD7, P9WPD8, P9WPD9, Q04671, Q0VQ74, Q54GU0, Q57486, Q62052, Q8MIQ9, Q9KQU7, A1JQP8, A4TJC7, A7FI95, A7MNK6, A9R9D6, B1JLH7, B2K3Q0, Q1C7V3, Q1CJ89, Q66AQ9, Q74U12, P75788, Q57898, Q9AV23, Q2W8Q3, Q6NE56, Q39593

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
HLTF	“up-regulates quantity by expression”	OCA2	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	OCA2	“transcriptional regulation”
MITF	“up-regulates quantity by expression”	OCA2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1505 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	179
Likely pathogenic	122
Uncertain significance	376
Likely benign	552
Benign	85

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013060	NM_000275.3(OCA2):c.2336del (p.Gly779fs)	Pathogenic
1074425	NC_000015.9:g.(?28263523)(28263723_?)del	Pathogenic
1074426	NC_000015.9:g.(?28171253)(28231809_?)del	Pathogenic
1098719	Single allele	Pathogenic
1098720	Single allele	Pathogenic
1284494	NM_000275.3(OCA2):c.163del (p.Ala55fs)	Pathogenic
1332871	NM_000275.3(OCA2):c.1951+1G>C	Pathogenic
1338408	NM_000275.3(OCA2):c.122del (p.Gly41fs)	Pathogenic
1370460	NC_000015.9:g.(?28269971)(28270068_?)del	Pathogenic
1388161	NM_000275.3(OCA2):c.1979G>A (p.Trp660Ter)	Pathogenic
1388959	NM_000275.3(OCA2):c.631C>G (p.Pro211Ala)	Pathogenic
1402367	NC_000015.9:g.(?28171253)(28171420_?)del	Pathogenic
1411558	NM_000275.3(OCA2):c.2244+1G>A	Pathogenic
1417098	NM_000275.3(OCA2):c.950del (p.Leu316_Leu317insTer)	Pathogenic
1435943	NM_000275.3(OCA2):c.1346dup (p.Thr450fs)	Pathogenic
1436215	NM_000275.3(OCA2):c.1044+2T>C	Pathogenic
1439928	NM_000275.3(OCA2):c.2338+1G>T	Pathogenic
1442379	NM_000275.3(OCA2):c.1611T>G (p.Tyr537Ter)	Pathogenic
1452282	NC_000015.9:g.(?28211816)(28277329_?)del	Pathogenic
1452544	NM_000275.3(OCA2):c.916del (p.Ala306fs)	Pathogenic
1453609	NC_000015.10:g.27955214_27955217del	Pathogenic
1453958	NC_000015.9:g.(?28228471)(28228649_?)del	Pathogenic
1454562	NM_000275.3(OCA2):c.2353_2356del (p.Ile785fs)	Pathogenic
1454819	NC_000015.9:g.(?28200284)(28200381_?)del	Pathogenic
1454821	NC_000015.9:g.(?28211816)(28235813_?)del	Pathogenic
1454822	NC_000015.9:g.(?28171253)(28235813_?)del	Pathogenic
1454882	NM_000275.3(OCA2):c.274del (p.Ser92fs)	Pathogenic
1456257	NM_000275.3(OCA2):c.1843-1G>T	Pathogenic
1458413	NM_000275.3(OCA2):c.1555del (p.Val519fs)	Pathogenic
1459895	NC_000015.9:g.(?28231713)(28235813_?)del	Pathogenic

SpliceAI

6186 predictions. Top by Δscore:

Variant	Effect	Δscore
15:27844954:AGTAC:A	donor_loss	1.0000
15:27844955:GTAC:G	donor_loss	1.0000
15:27844956:TACCT:T	donor_loss	1.0000
15:27844957:A:C	donor_loss	1.0000
15:27844958:C:T	donor_loss	1.0000
15:27955104:A:AC	donor_gain	1.0000
15:27955105:C:CC	donor_gain	1.0000
15:27955105:CT:C	donor_gain	1.0000
15:27955211:TCTGT:T	acceptor_loss	1.0000
15:27955212:CTGT:C	acceptor_gain	1.0000
15:27955213:TGT:T	acceptor_gain	1.0000
15:27955213:TGTCT:T	acceptor_loss	1.0000
15:27955215:TCTA:T	acceptor_loss	1.0000
15:27955216:C:CA	acceptor_loss	1.0000
15:27955216:C:CC	acceptor_gain	1.0000
15:27955217:T:A	acceptor_loss	1.0000
15:27957584:GTAC:G	donor_loss	1.0000
15:27957585:TAC:T	donor_loss	1.0000
15:27957587:C:CT	donor_loss	1.0000
15:27957731:CAGTT:C	acceptor_gain	1.0000
15:27957732:AGTT:A	acceptor_gain	1.0000
15:27957733:GTT:G	acceptor_gain	1.0000
15:27957734:TT:T	acceptor_gain	1.0000
15:27957735:TC:T	acceptor_loss	1.0000
15:27957736:C:CC	acceptor_gain	1.0000
15:27957737:T:C	acceptor_loss	1.0000
15:27983344:CCAT:C	donor_gain	1.0000
15:27983350:T:TA	donor_gain	1.0000
15:27983480:CAAC:C	acceptor_gain	1.0000
15:27983482:ACCT:A	acceptor_loss	1.0000

AlphaMissense

5427 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:27845021:G:C	N790K	0.999
15:27845021:G:T	N790K	0.999
15:27844964:A:C	F809L	0.998
15:27844964:A:T	F809L	0.998
15:27844966:A:G	F809L	0.998
15:27845002:C:G	A797P	0.998
15:27926171:A:G	W679R	0.998
15:27926171:A:T	W679R	0.998
15:27983394:C:T	G485E	0.998
15:27983395:C:A	G485W	0.998
15:27983445:A:G	L468P	0.998
15:27845001:G:T	A797E	0.997
15:27845034:C:T	G786D	0.997
15:27845046:C:T	G782E	0.997
15:27871175:G:C	N741K	0.997
15:27871175:G:T	N741K	0.997
15:27926151:A:C	F685L	0.997
15:27926151:A:T	F685L	0.997
15:27926153:A:G	F685L	0.997
15:27926237:C:G	G657R	0.997
15:27983395:C:G	G485R	0.997
15:27983395:C:T	G485R	0.997
15:27983420:G:C	N476K	0.997
15:27983420:G:T	N476K	0.997
15:27985106:T:A	D441V	0.997
15:27845019:A:T	V791D	0.996
15:27845048:G:C	N781K	0.996
15:27845048:G:T	N781K	0.996
15:27926154:A:C	F684L	0.996
15:27926154:A:T	F684L	0.996

dbSNP variants (sampled 300 via entrez): RS1000000182 (15:28056937 G>A), RS1000009450 (15:27841793 T>C), RS1000009742 (15:27989191 G>A,T), RS1000016905 (15:27967761 G>A,C), RS1000018212 (15:27906869 C>T), RS1000038625 (15:27822988 T>C), RS1000053911 (15:27881554 A>C,G), RS1000070501 (15:28063769 T>C,G), RS1000070735 (15:28088898 T>C), RS1000073147 (15:27767658 G>T), RS1000073922 (15:28095561 A>G), RS1000075706 (15:27900821 C>A), RS1000088836 (15:27795476 C>A), RS1000100184 (15:28003959 T>C,G), RS1000116727 (15:27980982 G>C)

Disease associations

OMIM: gene MIM:611409 | disease phenotypes: MIM:203200, MIM:203100, MIM:310700, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
oculocutaneous albinism type 2	Definitive	Autosomal recessive
oculocutaneous albinism	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
oculocutaneous albinism type 2	Definitive	AR

Mondo (6): oculocutaneous albinism type 2 (MONDO:0008746), oculocutaneous albinism (MONDO:0018910), congenital nystagmus (MONDO:0005712), hypophosphatasia (MONDO:0018570), albinism (MONDO:0043209), cone-rod dystrophy (MONDO:0015993)

Orphanet (5): Oculocutaneous albinism type 2 (Orphanet:79432), Oculocutaneous albinism (Orphanet:55), Hypophosphatasia (Orphanet:436), Cone rod dystrophy (Orphanet:1872), NON RARE IN EUROPE: Idiopathic infantile nystagmus (Orphanet:651)

HPO phenotypes

142 total (30 of 142 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000154	Wide mouth
HP:0000219	Thin upper lip vermilion
HP:0000303	Mandibular prognathia
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000539	Abnormality of refraction
HP:0000545	Myopia
HP:0000577	Exotropia
HP:0000613	Photophobia
HP:0000635	Blue irides
HP:0000639	Nystagmus
HP:0000687	Widely spaced teeth
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000748	Inappropriate laughter
HP:0000752	Hyperactivity
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000819	Diabetes mellitus
HP:0000823	Delayed puberty

GWAS associations

83 associations (top):

Study	Trait	p-value
GCST000117_3	Blue vs. green eyes	2.000000e-53
GCST000118_3	Blond vs. brown hair color	6.000000e-35
GCST000120_1	Blue vs. brown eyes	1.000000e-241
GCST000190_2	Black vs. blond hair color	2.000000e-24
GCST000191_7	Black vs. red hair color	6.000000e-20
GCST000490_2	Parkinson’s disease (age of onset)	3.000000e-06
GCST000707_5	Hair color	9.000000e-88
GCST000710_6	Eye color	1.000000e-300
GCST000710_8	Eye color	3.000000e-52
GCST001509_3	Vitiligo	4.000000e-08
GCST001723_1	Eye color	2.000000e-20
GCST001929_3	Eye color	1.000000e-07
GCST002875_33	Diisocyanate-induced asthma	7.000000e-14
GCST002906_1	Skin colour saturation	4.000000e-14
GCST003020_2	Red vs non-red hair color	2.000000e-06
GCST003021_7	Brown vs. non-brown hair color	2.000000e-06
GCST003022_7	Light vs. dark hair color	3.000000e-06
GCST003023_6	Blond vs non-blond hair color	9.000000e-07
GCST003061_7	Cutaneous malignant melanoma	2.000000e-11
GCST003264_238	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST003327_12	Squamous cell carcinoma	6.000000e-10
GCST003479_1	Hair color	5.000000e-104
GCST003655_6	Cutaneous squamous cell carcinoma	9.000000e-09
GCST003726_13	Basal cell carcinoma	8.000000e-17
GCST004142_19	Melanoma	2.000000e-11
GCST004661_2	Uveal melanoma	5.000000e-07
GCST004785_31	Vitiligo	9.000000e-14
GCST005093_9	Iris color (a* coordinate)	9.000000e-11
GCST005094_12	Iris color (L* coordinate)	2.000000e-06
GCST005096_6	Iris color (b* coordinate)	5.000000e-12

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0003949	eye color
EFO:0003924	hair color
EFO:0004847	age at onset
EFO:0006995	response to diisocyanate
EFO:0004713	FEV/FVC ratio
EFO:1001927	cutaneous squamous cell carcinoma
EFO:0004279	suntan
EFO:0009764	eye colour measurement
EFO:0010554	retinal vasculature measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000417	Albinism	C11.270.040; C16.320.290.040; C16.320.565.100.102; C16.320.850.080; C17.800.621.440.102; C17.800.827.080; C18.452.648.100.102
D016115	Albinism, Oculocutaneous	C11.270.040.545; C16.320.290.040.100; C16.320.565.100.102.100; C16.320.850.080.100; C17.800.621.440.102.100; C17.800.827.080.100; C18.452.648.100.102.100
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D007014	Hypophosphatasia	C16.320.565.618.482; C18.452.648.618.482
D020417	Nystagmus, Congenital	C10.292.562.675.300; C11.590.400.300; C16.614.643
C537730	Oculocutaneous albinism type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	5
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	4
Aflatoxin B1	increases methylation, affects methylation, decreases expression	3
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
propionaldehyde	increases expression	1
bisphenol A	affects methylation, affects cotreatment	1
butyraldehyde	increases expression	1
ferrous chloride	decreases expression	1
pentanal	increases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Aldehydes	increases expression	1
Arsenic	affects methylation	1
Etoposide	affects response to substance	1
Nickel	decreases expression	1
Niclosamide	increases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

84 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02531867	PHASE4	COMPLETED	Post-approval Clinical Study of Asfotase Alfa Treatment for Patients With Hypophosphatasia (HPP) in Japan
NCT04189315	PHASE4	WITHDRAWN	Relieving Burden of Hypophosphatasia in Adults With Functional Impairment Due to Chronic Disease
NCT06015750	PHASE4	WITHDRAWN	Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia
NCT06079281	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa
NCT06079359	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Study of ALXN1850 in Treatment-Naïve Pediatric Participants With HPP
NCT06079372	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Study of ALXN1850 in Pediatric Participants With HPP Previously Treated With Asfotase Alfa
NCT00001596	PHASE2	COMPLETED	Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
NCT01663935	PHASE2	TERMINATED	Vision Response to Dopamine Replacement
NCT00001866	PHASE2	COMPLETED	Eye Muscle Surgery to Treat Congenital Nystagmus
NCT00799942	PHASE2	TERMINATED	Open-lable Extension Study on Safety and Efficacy of Neramexane to Treat Congenital and Acquired Nystagmus
NCT00894075	PHASE2	WITHDRAWN	Safety and Efficacy Study of ENB-0040 in Juvenile Patients With Hypophosphatasia (HPP)
NCT00952484	PHASE2	COMPLETED	Safety and Efficacy of Asfotase Alfa in Juvenile Patients With Hypophosphatasia (HPP)
NCT01163149	PHASE2	COMPLETED	Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)
NCT01203826	PHASE2	COMPLETED	Extension Study of Protocol ENB-006-09 - Study of Asfotase Alfa in Children With Hypophosphatasia (HPP)
NCT01205152	PHASE2	COMPLETED	Extension Study of Protocol ENB-002-08 - Study of Asfotase Alfa in Infants and Young Children With Hypophosphatasia (HPP)
NCT01406977	PHASE2	COMPLETED	Dose Escalation Study to Evaluate the Safety and Tolerability of Multiple Infusions of BPS804 in Adults With Hypophosphatasia (HPP)
NCT02456038	PHASE2	COMPLETED	Safety and Efficacy of Asfotase Alfa in Patients With Hypophosphatasia (HPP)
NCT02797821	PHASE2	COMPLETED	Pharmacokinetic and Dose Response Study of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia (HPP)
NCT01176435	PHASE2	COMPLETED	Trial of L-DOPA as a Treatment to Improve Vision in Albinism
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT00739505	PHASE1	COMPLETED	Safety Study of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)
NCT04980248	PHASE1	COMPLETED	Study of ALXN1850 in Participants With Hypophosphatasia (HPP)
NCT00467831	PHASE1/PHASE2	TERMINATED	Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
NCT07313618	EARLY_PHASE1	RECRUITING	Safety and Efficacy of a Single Suprachoroidal Injection of JWK010 Gene Therapy in Subjects With Oculocutaneous Albinism Type 1 (OCA1)
NCT00001153	Not specified	COMPLETED	Visual Function and Ocular Pigmentation in Albinism
NCT00808106	Not specified	COMPLETED	Clinical, Cellular, and Molecular Investigation Into Oculocutaneous Albinism
NCT02200263	Not specified	COMPLETED	The Effects of Lutein and Zeaxanthin Supplementation on Vision in Patients With Albinism
NCT04068961	Not specified	COMPLETED	New Strategies of Genetic Study of Patients With Oculocutaneous Albinism
NCT06138509	Not specified	RECRUITING	Peripheral Serotonin and Albinism
NCT00001861	Not specified	COMPLETED	Screening for Studies on Nystagmus and Strabismus
NCT00702832	Not specified	COMPLETED	Effect of Vestibular Rehabilitation - a Randomized Controlled Trial
NCT00928954	Not specified	COMPLETED	Cross-over Comparison of Gabapentin and Memantine as Treatment for Acquired Nystagmus
NCT03603301	Not specified	UNKNOWN	Vision in Children Born to Opioid-dependent Methadone-maintained Mothers
NCT04770519	Not specified	RECRUITING	Genetic Studies of Strabismus, Nystagmus, and Associated Disorders
NCT07126938	Not specified	COMPLETED	Alcohol Impairment Detection in Healthy Adult Users With the Gaize Device
NCT07238387	Not specified	NOT_YET_RECRUITING	Evaluation of Nystagmus Examination Using Wearable AR Glasses in Vertigo Patients
NCT07583901	Not specified	COMPLETED	Effects of Gaze Stabalization Exercises and Optokinetic Training in Peripheral Vestibular Disorders
NCT07587528	Not specified	COMPLETED	Effects of Cervical and Oculomotor Exercises in Young Adults With Benign Paroxysmal Positional Vertigo
NCT01176266	PHASE2/PHASE3	COMPLETED	Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)
NCT00744042	PHASE1/PHASE2	COMPLETED	Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP)