PRAME

Summary

PRAME (PRAME nuclear receptor transcriptional regulator, HGNC:9336) is a protein-coding gene on chromosome 22q11.22, encoding Melanoma antigen preferentially expressed in tumors (P78395). Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex, which mediates ubiquitination of target proteins, leading to their degradation.

This gene encodes an antigen that is preferentially expressed in human melanomas and that is recognized by cytolytic T lymphocytes. It is not expressed in normal tissues, except testis. The encoded protein acts as a repressor of retinoic acid receptor, and likely confers a growth advantage to cancer cells via this function. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23532 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 9 total — 2 pathogenic
• GTEx eGene: eQTL in 9 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.90 (unconstrained)
• MANE Select transcript: NM_206956

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9336
Approved symbol	PRAME
Name	PRAME nuclear receptor transcriptional regulator
Location	22q11.22
Locus type	gene with protein product
Status	Approved
Aliases	CT130
Ensembl gene	ENSG00000185686
Ensembl biotype	protein_coding
OMIM	606021
Entrez	23532

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000405655

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 4, TSL 4: 1, TSL 5: 3

ENST00000405655, ENST00000398741, ENST00000398743, ENST00000402697, ENST00000403441, ENST00000406503, ENST00000420709, ENST00000438888, ENST00000439106, ENST00000442481, ENST00000476336, ENST00000485532, ENST00000492657, ENST00000543184

RefSeq mRNA: 11 — MANE Select: NM_206956 NM_001291715, NM_001291716, NM_001291717, NM_001291719, NM_001318126, NM_001318127, NM_006115, NM_206953, NM_206954, NM_206955, NM_206956

CCDS: CCDS13801

Canonical transcript exons

ENST00000405655 — 6 exons

Exon	Start	End
ENSE00001534682	22557545	22557580
ENSE00001555086	22556812	22556909
ENSE00003592330	22549726	22550334
ENSE00003642784	22550767	22551089
ENSE00003669064	22547701	22548643
ENSE00003849945	22558971	22559265

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 98.00.

FANTOM5 (CAGE): breadth broad, TPM avg 22.4439 / max 828.2856, expressed in 332 samples.

Highest expression (Bgee): testis, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, endometrium, adrenal gland cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PRAME is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

11 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	1.1e-67	-1.09	22:22556943:G:A
Brain Hypothalamus	eqtl	1.3e-15	+0.92	22:22546238:TAC:T
Testis	eqtl	3.9e-08	+0.19	22:22547106:A:G
Pituitary	eqtl	2.9e-05	-0.40	22:22553148:G:T
Brain Substantia nigra	eqtl	1.8e-04	+0.72	22:22559846:T:C
Adrenal Gland	sqtl	1.2e-03	+0.51	22:22554901:A:G
Brain Spinal cord cervical c-1	eqtl	1.5e-03	+0.60	22:22546238:TAC:T
Whole Blood	eqtl	4.6e-03	+0.81	22:22639114:T:G
Nerve Tibial	eqtl	8.7e-03	+0.23	22:22567243:A:AGGGG
Thyroid	eqtl	3.9e-02	-0.26	22:21646560:CA:C
Adrenal Gland	eqtl	4.0e-02	+0.37	22:22604686:C:G

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
193280	9.6806	103
193284	9.6506	315
209405	1.8235	172
193283	0.6738	76
193282	0.4172	73
193281	0.1601	54
193278	0.0382	20

Top tissues by expression

showing 100 of 131 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	98.00	gold quality
left testis	UBERON:0004533	97.76	gold quality
testis	UBERON:0000473	97.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	97.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.20	gold quality
endometrium	UBERON:0001295	77.43	gold quality
right adrenal gland cortex	UBERON:0035827	77.03	gold quality
right adrenal gland	UBERON:0001233	73.05	gold quality
left ovary	UBERON:0002119	68.94	gold quality
ovary	UBERON:0000992	67.99	gold quality
left adrenal gland	UBERON:0001234	67.95	gold quality
adrenal gland	UBERON:0002369	65.54	gold quality
right ovary	UBERON:0002118	65.24	gold quality
left adrenal gland cortex	UBERON:0035825	65.10	gold quality
adult mammalian kidney	UBERON:0000082	59.75	gold quality
cortex of kidney	UBERON:0001225	58.53	gold quality
kidney	UBERON:0002113	57.16	gold quality
mucosa of transverse colon	UBERON:0004991	56.82	gold quality
vermiform appendix	UBERON:0001154	55.88	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	54.53	gold quality
metanephros cortex	UBERON:0010533	54.33	gold quality
smooth muscle tissue	UBERON:0001135	53.27	gold quality
lymph node	UBERON:0000029	52.89	gold quality
gastrocnemius	UBERON:0001388	52.31	gold quality
fallopian tube	UBERON:0003889	51.98	gold quality
left uterine tube	UBERON:0001303	51.57	gold quality
heart left ventricle	UBERON:0002084	51.18	gold quality
lower esophagus mucosa	UBERON:0035834	50.87	gold quality
colonic epithelium	UBERON:0000397	50.79	gold quality
body of uterus	UBERON:0009853	50.45	gold quality
muscle of leg	UBERON:0001383	50.34	gold quality
duodenum	UBERON:0002114	49.90	gold quality
placenta	UBERON:0001987	49.67	gold quality
adrenal tissue	UBERON:0018303	48.90	gold quality
bone marrow cell	CL:0002092	48.77	silver quality
endocervix	UBERON:0000458	48.55	gold quality
right coronary artery	UBERON:0001625	48.26	gold quality
myometrium	UBERON:0001296	48.05	gold quality
sural nerve	UBERON:0015488	47.89	gold quality
heart	UBERON:0000948	47.85	gold quality
substantia nigra	UBERON:0002038	47.83	gold quality
right atrium auricular region	UBERON:0006631	47.01	gold quality
blood	UBERON:0000178	46.66	gold quality
stromal cell of endometrium	CL:0002255	46.28	gold quality
transverse colon	UBERON:0001157	46.26	gold quality
right uterine tube	UBERON:0001302	45.79	silver quality
multicellular organism	UBERON:0000468	45.71	gold quality
tonsil	UBERON:0002372	45.48	gold quality
popliteal artery	UBERON:0002250	45.22	gold quality
tibial artery	UBERON:0007610	45.14	gold quality
hypothalamus	UBERON:0001898	44.90	gold quality
right lobe of liver	UBERON:0001114	44.58	silver quality
left coronary artery	UBERON:0001626	44.57	gold quality
uterine cervix	UBERON:0000002	44.53	gold quality
apex of heart	UBERON:0002098	44.46	silver quality
gall bladder	UBERON:0002110	44.37	silver quality
colon	UBERON:0001155	44.21	gold quality
skin of leg	UBERON:0001511	43.80	gold quality
Ammon’s horn	UBERON:0001954	43.49	gold quality
intestine	UBERON:0000160	43.44	gold quality
small intestine	UBERON:0002108	42.79	gold quality
pituitary gland	UBERON:0000007	42.76	gold quality
adenohypophysis	UBERON:0002196	42.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	42.66	gold quality
body of pancreas	UBERON:0001150	42.55	gold quality
adipose tissue	UBERON:0001013	42.46	gold quality
zone of skin	UBERON:0000014	42.41	gold quality
thoracic aorta	UBERON:0001515	42.10	gold quality
muscle tissue	UBERON:0002385	42.03	gold quality
lower esophagus	UBERON:0013473	41.98	silver quality
spleen	UBERON:0002106	41.94	gold quality
ascending aorta	UBERON:0001496	41.90	gold quality
small intestine Peyer’s patch	UBERON:0003454	41.90	silver quality
lower esophagus muscularis layer	UBERON:0035833	41.89	silver quality
tibial nerve	UBERON:0001323	41.85	gold quality
urinary bladder	UBERON:0001255	41.81	gold quality
omental fat pad	UBERON:0010414	41.80	gold quality
fundus of stomach	UBERON:0001160	41.77	gold quality
body of stomach	UBERON:0001161	41.71	gold quality
muscle layer of sigmoid colon	UBERON:0035805	41.56	gold quality
esophagus	UBERON:0001043	41.50	gold quality
putamen	UBERON:0001874	41.48	silver quality
liver	UBERON:0002107	41.33	gold quality
esophagus mucosa	UBERON:0002469	41.22	gold quality
cerebellum	UBERON:0002037	40.83	gold quality
nucleus accumbens	UBERON:0001882	40.82	gold quality
cerebellar hemisphere	UBERON:0002245	40.79	gold quality
cerebellar cortex	UBERON:0002129	40.76	gold quality
descending thoracic aorta	UBERON:0002345	40.71	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	40.56	gold quality
caudate nucleus	UBERON:0001873	40.38	gold quality
skin of abdomen	UBERON:0001416	40.30	gold quality
right lobe of thyroid gland	UBERON:0001119	40.08	gold quality
right lung	UBERON:0002167	39.98	silver quality
upper lobe of left lung	UBERON:0008952	39.85	gold quality
right frontal lobe	UBERON:0002810	39.66	gold quality
thoracic mammary gland	UBERON:0005200	39.58	silver quality
stomach	UBERON:0000945	39.51	gold quality
amygdala	UBERON:0001876	39.41	gold quality
temporal lobe	UBERON:0001871	39.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-6	yes	78.93
E-GEOD-134144	yes	26.87
E-ANND-3	no	0.96

HPA expression

RNA tissue specificity: Tissue enriched

24 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Testis	tissue	37.7	high
Epididymis	tissue	9.2	not detected
Endometrium 1	tissue	3.2	not detected
Ovary	tissue	2.0	not detected
Adrenal gland	tissue	0.5	not detected
Pituitary gland	tissue	0.3
Cervix	tissue	0.2	not detected
Retina	tissue	0.2
Smooth muscle	tissue	0.2	not detected
Lung	tissue	0.2	not detected
Kidney	tissue	0.2	not detected
Thymus	tissue	0.2
Appendix	tissue	0.2	not detected
Skin 1	tissue	0.1	not detected
Lymph node	tissue	0.1	not detected
Cerebral cortex	tissue	0.1	not detected
Vagina	tissue	0.1	not detected
Adipose tissue	tissue	0.1	not detected
Colon	tissue	0.1	not detected
Spleen	tissue	0.1	not detected
Locus coeruleus	tissue	0.1
Tonsil	tissue	0.1	not detected
Cingulate cortex	tissue	0.1
Fallopian tube	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 67; highest nTPM — Dorsal funiculus (white matter) (0.4), Anterior cochlear nucleus, ventral (0.3), Medial olivary nucleus (0.3), Medial parabrachial nucleus (0.3), Principal sensory trigeminal nucleus (0.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, SOX9

miRNA regulators (miRDB)

Targeting PRAME by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

21 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-4724-5P	98.87	67.75	1324
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-3977	98.00	68.17	1500
HSA-MIR-618	97.62	67.46	861
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-4764-3P	96.81	67.94	580
HSA-MIR-632	96.08	67.17	798
HSA-MIR-1238-3P	95.27	62.25	552
HSA-MIR-1231	95.10	65.63	663

Functional genomics

gnomAD constraint: pLI 6.11e-05, LOEUF 0.9, missense Z -0.0136 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000405655 — one region, missense o/e 1.05.

Literature-anchored findings (GeneRIF, showing 40)

• expression of PRAME is an indicator of favorable prognosis and could be a useful tool for monitoring minimal residual disease in childhood AML. (PMID:11943337)
• PRAME gene expression in childhood acute lymphoblastic leukemia (PMID:12419593)
• PRAME is highly expressed in primary advanced neuroblastoma (PMID:15240516)
• The overexpression of PRAME protein frequently observed in human cancers confers growth or survival advantages by antagonizing retinoic acid receptor(RAR) signaling. (PMID:16179254)
• The results suggest that the analysis of PRAME protein may contribute for the distinction between normal and leukemic cells in chronic lymphoproliferative disorders(CLD), and that PRAME may be a potential target for therapy. (PMID:16620968)
• PRAME is expressed in acute myeloblastic leukaemia (PMID:16681423)
• Overexpression of PRAME was associated with childhood acute leukemia (PMID:16860864)
• PRAME is detected in one third of the cases with CLs. PRAME mRNA changes may be detected during the progression of these disorders and/or after therapy. PRAME mRNA may be a useful marker to detect the minimal residual disease and the response to therapy. (PMID:16914202)
• hypomethylation of PRAME up-regulates its expression in CML and might play a significant role in the progression of the disease (PMID:17382387)
• Changes in the methylation pattern in defined parts of the regulatory regions of PRAME are sufficient for its upregulation in cells usually not expressing the gene. (PMID:17534929)
• PRAME mRNA expression may be a useful prognostic and predictive marker for breast cancer. (PMID:17624586)
• PRAME expression is not associated with down-regulation of retinoic acid signaling in primary acute myeloid leukemia. (PMID:17693191)
• PRAME expression in acute leukemia may be a useful marker to detect the minimal residual disease and to determine the response to therapy in acute leukemia patients. (PMID:18088454)
• PRAME gene was overexpressed in adult acute leukemia patients and leukemia cell-lines. (PMID:18088461)
• We conclude that HCL and CLL differ in PRAME overexpression, and that basal normal expression of PRAME may limit its usefulness for following patients with minimal residual CLL or HCL. (PMID:18295331)
• Loss of PRAME is associated with childhood acute myeloid leukemia. (PMID:18452107)
• The significant inverse correlation between the degree of methylation and PRAME expression suggests a causal role of DNA methylation in PRAME regulation. (PMID:18587578)
• Multivariable analysis indicated that PRAME is an independent marker of shortened metastasis-free interval in patients who did not receive adjuvant chemotherapy. PRAME expression was associated with tumour grade and negative oestrogen receptor status (PMID:18648365)
• the 4 biomarkers CLU, ITGB3, PRAME and CAPG may be used as prognostic factors for patients with stage III serous ovarian adenocarcinomas. (PMID:18709641)
• Low PRAME expression defines a subgroup of patients with acute promyelocytic leukemia with a short relapse-free survival (PMID:18815192)
• quantified both WT1 and PRAME transcript levels in the bone marrow of AML patients. Dynamic patterns of WT1 and PRAME during follow-up showed that a consistent elevation or a rise over time to exceed the normal range predicted clinical relapse (PMID:18950857)
• These results provide evidence for spontaneous T cell reactivity against multiple epitopes of PRAME in lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia (PMID:18988867)
• Quantitative real-time PCR revealed that ZNF280A, ZNF280B, and PRAME mRNA expression was significantly lower in the 22q11 deletion cases compared to non-deleted cases (PMID:19027161)
• PRAME mRNA could be used to monitor minimal residual disease in newly diagnosed acute myeloid leukemia patients. (PMID:19035174)
• E2F4, PHACTR3, PRAME family member and CDH12 most probably play important role in non-small-cell lung cancer geneses (PMID:19473719)
• PRAME expression in DLBCL correlates with response to anthracycline containing chemotherapy. (PMID:19474511)
• PRAME inhibits myeloid differentiation in certain myeloid leukemias, and that its function in these cells is lineage and phenotype dependent. (PMID:19625708)
• The PRAME transcript was highly expressed in acute myeloid leukemia patients and was a favorable marker of prognosis. (PMID:20376794)
• The level of prame gene transcript increases in chronic myeloid leukemia which associates with disease progression. (PMID:20723287)
• Results showed the expression of MCSP and PRAME in conjunctival melanoma and benign conjunctival nevi and showed that MCSP and PRAME were differentially expressed in both and can help to differentiate the lesions diagnostically. (PMID:20805128)
• PRAME may be involved in the tumorigenic process in a wide range of cancers, at least in part by blocking the tumor suppressor pathway mediated by TRAIL expression. (PMID:20838376)
• The cytotoxic activity of our PRAME-specific CTLs was directed not only against leukemic blasts, but also against leukemic progenitor cells as assessed by colony-forming-inhibition assays, which have been implicated in leukemia relapse. (PMID:21278353)
• the expansion of the PRAME family occurred in both autosomes and sex chromosomes (PMID:21347312)
• PRAME plays an important role in disease progression in acute leukemia. (PMID:21550659)
• PRAME expression might be related to distinct patterns of tumorigenesis (PMID:21691740)
• The authors applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. (PMID:21822215)
• Studies suggest that activated human gammadelta T cells can efficiently present PRAME and STEAP1-derived epitopes and allow breaking tolerance against these tumor-associated self-antigens. (PMID:21928126)
• PRAME effectively differentiates mullerian carcinoma from malignant mesothelioma at the mRNA and protein levels. (PMID:22261449)
• NYESO-1/LAGE-1s and PRAME are targets for antigen specific T cells in chondrosarcoma following treatment with 5-Aza-2-deoxycitabine (PMID:22384167)
• these results suggest that PRAME plays an important role in cell proliferation and disease progression in osteosarcoma. (PMID:22390931)

Cross-species orthologs

0 orthologs

Paralogs (24): PRAMEF1 (ENSG00000116721), PRAMEF12 (ENSG00000116726), PRAMEF2 (ENSG00000120952), LRRC14 (ENSG00000160959), PRAMEF8 (ENSG00000182330), LRRC14B (ENSG00000185028), PRAMEF10 (ENSG00000187545), PRAMEF20 (ENSG00000204478), PRAMEF17 (ENSG00000204479), PRAMEF19 (ENSG00000204480), PRAMEF14 (ENSG00000204481), PRAMEF15 (ENSG00000204501), PRAMEF9 (ENSG00000204505), PRAMEF7 (ENSG00000204510), PRAMEF25 (ENSG00000229571), PRAMEF6 (ENSG00000232423), PRAMEF33 (ENSG00000237700), PRAMEF11 (ENSG00000239810), PRAMEF4 (ENSG00000243073), PRAMEF5 (ENSG00000270601), PRAMEF27 (ENSG00000274764), PRAMEF13 (ENSG00000279169), PRAMEF18 (ENSG00000279804), PRAMEF26 (ENSG00000280267)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Rattus norvegicus	Q569B5	96.6%	Diamond
Mus musculus	Q8VC16	96.6%	Diamond
Bos taurus	A5PJJ5	95.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ZNF280A	protein-coding	129025
ZNF280B	protein-coding	140883
IGL	protein-coding	3535
PRAME-AS	ncRNA	648691
PPM1F-AS1	ncRNA	100286925
IGLL5	protein-coding	100423062
MIR5571	ncRNA	100847006
LL22NC03-102D1.18	ncRNA	105372949
RSPH14	protein-coding	27156
GNAZ	protein-coding	2781
MIR650	ncRNA	723778
VPREB1	protein-coding	7441
TOP3B	protein-coding	8940
GGTLC2	protein-coding	91227
PPM1F	protein-coding	9647

Protein

Protein identifiers

Melanoma antigen preferentially expressed in tumors — P78395 (reviewed: P78395)

Alternative names: Opa-interacting protein 4, Preferentially expressed antigen of melanoma

All UniProt accessions (6): B5MCY4, B5MD04, E7EMH2, E7EW99, H7C2P3, P78395

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex, which mediates ubiquitination of target proteins, leading to their degradation. The CRL2(PRAME) complex mediates ubiquitination and degradation of truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding. In the nucleus, the CRL2(PRAME) complex is recruited to epigenetically and transcriptionally active promoter regions bound by nuclear transcription factor Y (NFY) and probably plays a role in chromstin regulation. Functions as a transcriptional repressor, inhibiting the signaling of retinoic acid through the retinoic acid receptors RARA, RARB and RARG: prevents retinoic acid-induced cell proliferation arrest, differentiation and apoptosis.

Subunit / interactions. Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter PRAME. Interacts with RARA (via the ligand-binding domain); the interaction is direct and ligand (retinoic acid)-dependent. Interacts with EZH2; required to repress RAR signaling.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Golgi apparatus. Cell membrane.

Tissue specificity. Expressed in testis. Detected in samples of kidney, brain and skin.

Induction. Up-regulated in response to interferon gamma (IFNG) treatment and exposure to bacterial PAMPs (pathogen associated molecular patterns).

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Tumor antigen recognized by cytolytic T lymphocytes.

Similarity. Belongs to the PRAME family.

RefSeq proteins (11): NP_001278644, NP_001278645, NP_001278646, NP_001278648, NP_001305055, NP_001305056, NP_006106, NP_996836, NP_996837, NP_996838, NP_996839* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026271	PRAME	Family
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050694	LRRC14/PRAME	Family

Pfam: PF27089, PF27091

UniProt features (19 total): repeat 9, mutagenesis site 3, modified residue 2, sequence variant 2, chain 1, region of interest 1, sequence conflict 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78395-F1	81.29	0.49

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; plasma membrane

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

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

Post-translational modifications (2)

Type	Positions
Phosphoserine	9, 16

Mutagenesis-validated functional residues (3)

Position	Phenotype
26–30	impaired formation of the crl2(prame) complex.
48–49	impaired formation of the crl2(prame) complex.
470–471	loss of interaction with rara and defective in repressing rara signaling.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 138 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_52, LI_WILMS_TUMOR, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_RETINOIC_ACID_RECEPTOR_SIGNALING_PATHWAY, MODULE_16, HATADA_METHYLATED_IN_LUNG_CANCER_DN, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_4NM_UP, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_1_UP, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, MODULE_66, MODULE_118, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_RETINOIC_ACID_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS

GO Biological Process (12): protein polyubiquitination (GO:0000209), DNA-templated transcription (GO:0006351), apoptotic process (GO:0006915), positive regulation of cell population proliferation (GO:0008284), cell differentiation (GO:0030154), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of cell differentiation (GO:0045596), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of retinoic acid receptor signaling pathway (GO:0048387), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627), protein ubiquitination (GO:0016567)

GO Molecular Function (3): nuclear retinoic acid receptor binding (GO:0042974), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), Cul2-RING ubiquitin ligase complex (GO:0031462), chromosome (GO:0005694)

GO top-level categories

40 GO namespaces:

Category	Terms
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
protein ubiquitination	1
gene expression	1
RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular developmental process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
cell differentiation	1
regulation of cell differentiation	1
negative regulation of cellular process	1
negative regulation of developmental process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
retinoic acid receptor signaling pathway	1
regulation of retinoic acid receptor signaling pathway	1
negative regulation of intracellular signal transduction	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
protein modification by small protein conjugation	1
nuclear receptor binding	1
enzyme-substrate adaptor activity	1
binding	1
chromosome	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
membrane	1
cell periphery	1
cullin-RING ubiquitin ligase complex	1
intracellular membraneless organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 22 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of DNA-templated transcription	BP	direct assay
negative regulation of apoptotic process	BP	direct assay
negative regulation of cell differentiation	BP	direct assay
negative regulation of retinoic acid receptor signaling pathway	BP	direct assay
positive regulation of cell population proliferation	BP	direct assay
proteasome-mediated ubiquitin-dependent protein catabolic process	BP	direct assay
protein polyubiquitination	BP	direct assay
Cul2-RING ubiquitin ligase complex	CC	direct assay
chromatin	CC	direct assay
nucleus	CC	direct assay
plasma membrane	CC	direct assay
nuclear retinoic acid receptor binding	MF	direct assay
ubiquitin-like ligase-substrate adaptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,209 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRAME	OIP5	O43482	790
PRAME	TRIP6	Q15654	765
PRAME	CTAG1A	P78358	750
PRAME	EXOSC8	Q96B26	727
PRAME	MAGEA4	P43358	702
PRAME	MAGEA3	P43357	700
PRAME	WT1	P19544	655
PRAME	MAGEA1	P43355	652
PRAME	ZNF280B	Q86YH2	643
PRAME	PKM	P14618	569
PRAME	MAGED4B	Q96JG8	566
PRAME	ZNF280A	P59817	556
PRAME	HLA-A	P01891	547
PRAME	BRAF	P15056	527
PRAME	ABCB5	Q2M3G0	504

IntAct

Human interaction partners of PRAME in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

15 partners by confidence:

Partner	Interaction type	MIscore	Records
CUL2	association	0.830	7
ELOC	association	0.740	4
FSCN3	association	0.530	1
AARSD1	physical association	0.400	1
HSP90AB1	physical association	0.400	1
NUDCD3	physical association	0.400	1
PPP5C	physical association	0.400	1
PSMD2	physical association	0.400	1
UBE2F	physical association	0.370	1
EEF1D	association	0.350	2
H4C16	association	0.350	1
POTEE	association	0.350	1
RBX1	association	0.350	1
CCDC28B	physical association	0.000	1
WHR1	physical association	0.000	1

BioGRID (153 interactions; top human partners by supporting records): CUL2 (Affinity Capture-MS; 10 records), TCEB2 (Affinity Capture-MS; 8 records), TCEB1 (Affinity Capture-Western; 7 records), LAGE3 (Affinity Capture-MS; 5 records), OSGEP (Affinity Capture-MS; 5 records), COPS2 (Affinity Capture-MS; 3 records), IFT81 (Affinity Capture-MS; 3 records), QTRT1 (Affinity Capture-MS; 3 records), RARA (Affinity Capture-Western; 3 records), RBX1 (Affinity Capture-MS; 3 records), ZNF562 (Affinity Capture-MS; 3 records), AZIN2 (Affinity Capture-MS; 2 records), CDKN2A (Affinity Capture-Western; 2 records), EEF1D (Affinity Capture-MS; 2 records), FBXL12 (Affinity Capture-Western; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
SOX9	“down-regulates quantity by repression”	PRAME	“transcriptional regulation”

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
PRAME complex	7	LAGE3, OSGEP, PRAME, RBX1, CUL2, ELOB, ELOC
PRAME-ElonginBC ubiquitin ligase	3	ELOC, PRAME, ELOB
PRAME-Cullin2 ubiquitin ligase complex	2	CUL2, PRAME

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neddylation	5	23.7×	8e-05
Antigen processing: Ubiquitination & Proteasome degradation	5	18.6×	1e-04

Disease & clinical

Genetic variants

Variant evidence for PRAME: 9 ClinVar records (2 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
816560	GRCh37/hg19 22q11.21-11.22(chr22:21947428-22962196)x1	Pathogenic	criteria provided, single submitter	1
2663782	NC_000022.10:g.(?21797384)(23630313_?)del	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PRAME’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 410):

Position(s)	Effect	Δscore	Sites
22:22550335	acceptor_loss	1.0000	2
22:22550765–22550766	donor_loss	1.0000	5
22:22548644–22548645	acceptor_loss	0.9900	6
22:22549724–22549725	donor_loss	0.9900	5
22:22550335–22550336	acceptor_loss	0.9900	4
22:22550337	acceptor_gain	0.9900
22:22551090	acceptor_gain	0.9900
22:22551090–22551091	acceptor_loss	0.9900	5
22:22551100	acceptor_gain	0.9900
22:22557543–22557544	donor_loss	0.9900	5

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Skin Cutaneous Melanoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	4.96e-07
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.00056

Disease associations

OMIM: gene MIM:606021 | disease phenotypes: MIM:611867

GenCC curated gene-disease

Mondo (1): chromosome 22q11.2 deletion syndrome, distal (MONDO:0012740)

Orphanet (1): Distal 22q11.2 microdeletion syndrome (Orphanet:261330)

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C567511	Chromosome 22q11.2 Deletion Syndrome, Distal *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases reaction, affects cotreatment, decreases expression, affects binding, decreases reaction	4
bisphenol A	decreases reaction, affects binding, affects folding, affects reaction	2
bisphenol AF	affects binding, affects reaction, affects folding, increases reaction	2
Valproic Acid	increases expression, increases methylation	2
TAK-243	increases sumoylation	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	decreases methylation	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
nickel acetate	decreases reaction, increases expression, decreases expression	1
perfluorobutanesulfonic acid	increases expression	1
bisphenol S	affects binding, decreases reaction	1
(+)-JQ1 compound	decreases expression	1
Alitretinoin	affects binding, increases reaction	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cannabidiol	decreases expression	1
Choline	affects expression	1
Doxorubicin	increases expression	1
Progesterone	affects cotreatment, decreases expression	1
Tamoxifen	affects binding, decreases reaction	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases activity, affects binding, increases reaction	1
Tunicamycin	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Metribolone	affects binding, affects folding, decreases reaction	1
Aflatoxin B1	decreases methylation	1
Cyproterone Acetate	affects binding, affects folding, increases reaction	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7J7	Ubigene A-375 PRAME KO	Cancer cell line	Female
CVCL_D8TN	Ubigene HCT 116 PRAME KO	Cancer cell line	Male
CVCL_E1GM	Abcam U2OS PRAME KO	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.