GeneBe

OCA2

protein-coding

OCA2 melanosomal transmembrane protein

Gene summary

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. [provided by RefSeq, Jul 2014]

Previous symbols:
  • D15S12
  • P
  • EYCL3
  • EYCL2

MANE transcript

NM_000275.3

Inheritance

AR, AD

ClinVar variants

P:347U:338B:365

Top phenotype

Albinism, oculocutaneous, type II; Albinism, brown oculocutaneous; Skin/hair/eye pigmentation 1

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr15:27,754,875-28,099,315

External References & Databases

Ensembl (ENSG00000104044)NCBI Gene (4948)OMIM (611409)HGNC:8101GenCCUniProt (Q04671)AlphaFoldClinVar (OCA2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~344.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oculocutaneous albinism type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008746

Submitter: G2P

oculocutaneous albinism type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008746

Submitter: Orphanet

oculocutaneous albinism type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008746

Submitter: ClinGen

Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders in which the biosynthesis of melanin pigment is reduced in the skin, hair, and eyes. Phenotypes associated include iris hypopigmentation, reduction in hair, skin, and eye pigment, abnormality of the optic nerve, nystagmus, photophobia, strabismus, and visual impairment (PMID:17980020). OCA is further broken down by type based on phenotypic differences. Oculocutaneous albinism type 2 is less severe than type 1 with skin and hair pigmentation ranging from minimal to near normal. Variants in OCA2 were first reported in relation to OCA2 in 1993 by Rinchik et al (PMID:8421497). Variants in OCA2 account for approximately 30% of worldwide cases of oculocutaneous albinism type 2 (at least 154 unique variants have been reported) (PMID:32963319). Evidence from 26 probands in 7 publications have been included in this curation, representing 31 unique variants (missense, nonsense, frameshift, and splice site) (PMIDs:115712365, 1906277, 33612058, 19865097, 28726809, 29345414, 33808351). Of note, the most common OCA2 variant among African individuals with oculocutaneous albinism, previously referred to in the literature as Brown oculocutaneous albinism [MIM:203200], is a 2.7 kb deletion; this variant is thought to account for ~20% of African cases (PMID:21085994). Please note that because the pigmentary phenotype due to pathogenic variants in OCA2 and other OCA genes can appear different in individuals of African descent. Per ClinGen Lumping and Splitting guidelines, the General Gene Curation Expert Panel has not identified a difference in phenotypes associated with both disease entities or types of variants associated with either presentation. Therefore, the GCEP has decided to lump this entity into this curation. The gene-disease relationship between oculocutaneous albinism type 2 and OCA2 is supported by evidence for protein interaction in melanocytes between the P protein encoded by OCA2 and both tyrosinase, and tyrosinase related protein 1 (encoded by two other genes, TYR and TYRP1, known to also be associated with oculocutaneous albinism) (PMID:19060277). Additionally, there are multiple animal models available to support this gene-disease relationship, including mice (PMIDs:1495987, 1509264, 8421497), German Spitz dogs (PMID:28973042), and Rhesus macaques (PMID:32259106). In summary there is definitive evidence supporting a gene-disease relationship between variants in OCA2 and oculocutaneous albinism type 2. This classification has been approved by the ClinGen General Gene Curation Expert Panel on 8/25/2021.

oculocutaneous albinismLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018910

Submitter: PanelApp Australia

oculocutaneous albinism type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008746

Submitter: Ambry Genetics

oculocutaneous albinism type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008746

Submitter: Labcorp Genetics (formerly Invitae)

oculocutaneous albinism type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008746

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Albinism, oculocutaneous, type II; Albinism, brown oculocutaneous; Skin/hair/eye pigmentation 1AD/AR

Manifestation: Dermatologic; Ophthalmologic

Intervention: General

Rationale: In Albinism, oculocutaneous, type II; Albinism, brown oculocutaneous, 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; Skin/hair/eye pigmentation 1 is a susceptibility factor locus for a multifactorial disease (melanoma)

Refs: 14904868; 687204; 7920637; 8302318; 7874125; 7762554; 7887411; 8723691; 10649493; 11179026; 12163334; 14704187; 15889046; 16341609; 17236130; 17952075; 18449927; 18680187; 20861488; 21471978; 21085994; 23103111Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OCA2 variants in ClinVar

23 Conditions Cataloged
not providedTotal: 1191
Tyrosinase-positive oculocutaneous albinismTotal: 270
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYESTotal: 158
Inborn genetic diseasesTotal: 94
not specifiedTotal: 87
OCA2-related disorderTotal: 71
Oculocutaneous albinismTotal: 48
Nonsyndromic Oculocutaneous AlbinismTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000275.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
6
clinvar
11
clinvar
316
clinvar
9
clinvar
 343
missense
18
clinvar
109
clinvar
323
clinvar
37
clinvar
3
clinvar
 490
nonsense
27
clinvar
11
clinvar
2
clinvar
 40
start loss
1
clinvar
 1
frameshift
60
clinvar
43
clinvar
2
clinvar
 105
splice donor/acceptor (+/-2bp)
29
clinvar
42
clinvar
 71
Total135212338353121050

Highest pathogenic variant AF is 0.0059140692

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000275.3RefSeqNP_000266.223MANE Select
ENST00000354638.8EnsemblENSP00000346659.323MANE Select
NM_001300984.2RefSeqNP_001287913.122Standard
ENST00000353809.10EnsemblENSP00000261276.822Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
oca2Danio rerio

Structure: melanocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Prader-Willi and Angelman Syndrome
  • Metabolism of amino acids and derivatives
  • Tyrosine metabolism
  • Biopterin metabolism
  • Metabolism

Biological Process

  • eye pigment biosynthetic process
  • spermatid development
  • cell population proliferation
  • tyrosine transport
  • melanocyte differentiation

Molecular Function

  • transporter activity
  • L-tyrosine transmembrane transporter activity
  • protein binding

Cellular Component

  • cytoplasm
  • lysosomal membrane
  • endoplasmic reticulum membrane
  • endosome membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000354638
Coding exons
23
Length
344484
Individuals with no LoFs
125641
Homozygous LoFs
0
Heterozygous LoFs
107
Defined
125748
p
0.000426
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.8335354831.110.00003195393
Missense (PolyPhen)204172.731.1812047
Synonymous-1.422322061.130.00001541750
Loss of Function2.322743.50.6210.00000210501

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00430.0030notable
Latino/Admixed American0.000670.00052rare
Ashkenazi Jewish00.0absent
East Asian0.000440.00044rare
Finnish00.0absent
European (Non-Finnish)0.000270.00026rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Could be involved in the transport of tyrosine, the precursor to melanin synthesis, within the melanocyte. Regulates the pH of melanosome and the melanosome maturation. One of the components of the mammalian pigmentary system. Seems to regulate the post-translational processing of tyrosinase, which catalyzes the limiting reaction in melanin synthesis. May serve as a key control point at which ethnic skin color variation is determined. Major determinant of brown and/or blue eye color. {ECO:0000269|PubMed:11310796, ECO:0000269|PubMed:15262401, ECO:0000269|PubMed:18252222, ECO:0000269|PubMed:22234890, ECO:0000269|PubMed:7601462}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:10649493, ECO:0000269|PubMed:10671067, ECO:0000269|PubMed:10987646, ECO:0000269|PubMed:12713581, ECO:0000269|PubMed:12727022, ECO:0000269|PubMed:12876664, ECO:0000269|PubMed:17385796, ECO:0000269|PubMed:23504663, ECO:0000269|PubMed:7762554, ECO:0000269|PubMed:7874125, ECO:0000269|PubMed:9259203}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.366

Intolerance Scores

LoFtool
0.0878
RVIS EVS
0.13
RVIS percentile EVS
62.75

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.208

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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