PRAM1

Summary

PRAM1 (PML-RARA regulated adaptor molecule 1, HGNC:30091) is a protein-coding gene on chromosome 19p13.2, encoding PML-RARA-regulated adapter molecule 1 (Q96QH2). May be involved in myeloid differentiation.

The protein encoded by this gene is similar to FYN binding protein (FYB/SLAP-130), an adaptor protein involved in T cell receptor mediated signaling. This gene is expressed and regulated during normal myelopoiesis. The expression of this gene is induced by retinoic acid and is inhibited by the expression of PML-RARalpha, a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha).

Source: NCBI Gene 84106 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 147 total
• MANE Select transcript: NM_032152

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30091
Approved symbol	PRAM1
Name	PML-RARA regulated adaptor molecule 1
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	PML-RAR
Ensembl gene	ENSG00000133246
Ensembl biotype	protein_coding
OMIM	606466
Entrez	84106

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000423345, ENST00000594696, ENST00000599698, ENST00000600262, ENST00000880309

RefSeq mRNA: 1 — MANE Select: NM_032152 NM_032152

CCDS: CCDS45954

Canonical transcript exons

ENST00000423345 — 10 exons

Exon	Start	End
ENSE00000910003	8491100	8491157
ENSE00000910004	8497764	8497840
ENSE00000910005	8498223	8498289
ENSE00000910006	8498376	8499780
ENSE00003023811	8502565	8502640
ENSE00003114924	8490056	8490226
ENSE00003552146	8490338	8490372
ENSE00003598301	8490476	8490509
ENSE00003667996	8490887	8490995
ENSE00003679988	8490594	8490756

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 98.06.

FANTOM5 (CAGE): breadth broad, TPM avg 10.1250 / max 586.0405, expressed in 406 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178953	7.9228	390
178952	2.2022	285

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.06	gold quality
leukocyte	CL:0000738	97.78	gold quality
granulocyte	CL:0000094	96.99	gold quality
blood	UBERON:0000178	93.43	gold quality
bone marrow cell	CL:0002092	93.32	gold quality
trabecular bone tissue	UBERON:0002483	91.03	gold quality
bone marrow	UBERON:0002371	87.77	gold quality
spleen	UBERON:0002106	85.78	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.05	gold quality
upper lobe of left lung	UBERON:0008952	83.39	gold quality
spinal cord	UBERON:0002240	83.21	gold quality
right lung	UBERON:0002167	83.15	gold quality
vermiform appendix	UBERON:0001154	81.89	gold quality
upper lobe of lung	UBERON:0008948	81.49	gold quality
caecum	UBERON:0001153	77.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.83	silver quality
substantia nigra	UBERON:0002038	76.80	gold quality
sural nerve	UBERON:0015488	76.68	gold quality
right uterine tube	UBERON:0001302	75.38	gold quality
midbrain	UBERON:0001891	75.38	gold quality
right lobe of liver	UBERON:0001114	74.78	gold quality
hypothalamus	UBERON:0001898	74.49	gold quality
lung	UBERON:0002048	73.71	gold quality
amygdala	UBERON:0001876	73.44	gold quality
tibial nerve	UBERON:0001323	72.61	gold quality
cerebellar hemisphere	UBERON:0002245	72.61	gold quality
cerebellar cortex	UBERON:0002129	72.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	72.46	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.42	gold quality
myocardium	UBERON:0002349	72.00	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	30.01
E-MTAB-6678	yes	25.96
E-ANND-3	yes	17.77
E-MTAB-9067	yes	13.26
E-MTAB-9801	yes	6.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HDAC3

miRNA regulators (miRDB)

1 targeting PRAM1, 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-7108-5P	96.42	66.17	598

Literature-anchored findings (GeneRIF, showing 15)

• PRAM-1 is required for optimal integrin-dependent neutrophil function. (PMID:15572693)
• Caspase 3-cleaved SH3 domain of HIP-55 is likely involved in PRAM-1-mediated JNK activation upon arsenic trioxide-induced differentiation of NB4 cells. (PMID:15637062)
• The use of reverse-transcription polymerase chain reaction for the detection of the PML-RARA and RARA-PML fusion genes that allow for monitoring of acute myelocytic leukemia. (PMID:16502581)
• PML-RARalpha fusion transcripts have been shown to be useful markers for establishing the diagnosis and for monitoring the response to treatment of acute promyelocytic leukemia. (PMID:16502582)
• Interaction of PRAM-1 and hSH3 domains of adhesion and degranulation promoting adapter protein (ADAP) with phosphatidylcholine-containing liposomes is observed upon incorporation of phosphatidylserine or phosphoinositides into the membrane bilayer. (PMID:16831444)
• hidden abnormalities and novel disease-related genomic changes occur in t(15;17)translocation in acute promyelocytic leukemia formation of PML-RARA gene (PMID:19109227)
• We conclude that our sp-RQ-PCR is specific enough to identify various forms of PML-RARalpha and yields no false-positive results. (PMID:19623654)
• autophagy contributes to the anti-apoptotic function of the PML-RARalpha protein through inhibiting the Akt/mTOR pathway (PMID:21673516)
• The MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of acute promyelocytic leukemia differentiation. (PMID:25126724)
• The 3-plex RT-qPCR assay is a specific, sensitive, stable, and cost-effective method that can be used for the rapid diagnosis and treatment monitoring of acute promyelocytic leukemia with PML-RARa (PMID:25815789)
• Our results show that the pretreatment PML-RARA molecular burden could therefore be used to improve risk stratification in order to develop more individualized treatment regimens for high-risk APL cases. (PMID:25944686)
• This study establishes PML as an important regulator of NF-kappaB and demonstrates that PML-RARalpha dysregulates NF-kappaB. (PMID:28317833)
• we diagnosed a spinal promyelocytic sarcoma as a manifestation of acute promyelocytic leukaemia with M3 morphology according to the French-American-British classification with t(15;17)(q22;q21) and PML-RARA fusion gene (PMID:28431836)
• NRF2 activation induced by PML-RARalpha promotes microRNA 125b-1 expression and confers resistance to chemotherapy in acute promyelocytic leukemia. (PMID:34047481)
• KDM5A suppresses PML-RARalpha target gene expression and APL differentiation through repressing H3K4me2. (PMID:34448811)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pram1	ENSMUSG00000032739

Paralogs (2): FYB1 (ENSG00000082074), FYB2 (ENSG00000187889)

Protein

Protein identifiers

PML-RARA-regulated adapter molecule 1 — Q96QH2 (reviewed: Q96QH2)

All UniProt accessions (2): Q96QH2, M0R149

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in myeloid differentiation. May be involved in integrin signaling in neutrophils. Binds to PtdIns(4)P.

Subunit / interactions. Interacts with SKAP2, LCP2 and DBNL. May interact with LYN. Interacts with NEK6.

Tissue specificity. Expressed in peripheral blood leukocytes and bone marrow. Expressed in monocytes, and to a lesser extent in granulocytes and lymphocytes. Not expressed in non hematopoietic tissues except in lung.

Post-translational modifications. May be phosphorylated on tyrosines.

Domain organisation. The SH3 domain binds to PtdIns(4)P.

Induction. Down-regulated by the PML-RARA oncogene, a fusion protein expressed in a vast majority of acute promyelocytic leukemia. Up-regulated by retinoic acid or arsenic trioxide in cells expressing PML-RARA.

Polymorphism. Some transcripts displayed additional 12 amino acid repeats of K-P-P-[PQ]-P-[EQ]-[VAF]-T-D-L-P-K. We cannot rule out that they may represent genetic variants.

RefSeq proteins (1): NP_115528* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR029294	hSH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR043443	FYB1/2-like	Family

Pfam: PF14603

UniProt features (22 total): compositionally biased region 6, repeat 4, sequence variant 4, sequence conflict 3, region of interest 2, chain 1, modified residue 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96QH2-F1	54.21	0.09

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 (1): 340

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 137 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_EXOCYTOSIS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_MYELOID_LEUKOCYTE_ACTIVATION, GOBP_SECRETION, GOBP_REGULATION_OF_REGULATED_SECRETORY_PATHWAY, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (4): integrin-mediated signaling pathway (GO:0007229), regulation of neutrophil degranulation (GO:0043313), T cell receptor signaling pathway (GO:0050852), protein localization to plasma membrane (GO:0072659)

GO Molecular Function (3): lipid binding (GO:0008289), protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cell surface receptor signaling pathway	1
regulation of myeloid leukocyte mediated immunity	1
regulation of leukocyte degranulation	1
neutrophil degranulation	1
regulation of immune response	1
antigen receptor-mediated signaling pathway	1
protein localization to membrane	1
protein localization to cell periphery	1
kinase binding	1
membrane	1
cell periphery	1
cellular_component	1

Protein interactions and networks

STRING

854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRAM1	RARA	P10276	898
PRAM1	NCOR2	Q9Y618	789
PRAM1	SKAP2	O75563	766
PRAM1	DNMT3A	Q9Y6K1	721
PRAM1	ZBTB16	Q05516	721
PRAM1	DNMT1	P26358	686
PRAM1	PML	P29590	660
PRAM1	RUNX1	Q01196	658
PRAM1	NCOR1	O75376	656
PRAM1	RUNX1T1	Q06455	612
PRAM1	TRIM24	O15164	581
PRAM1	RARS1	P54136	563
PRAM1	UBE2I	P50550	515
PRAM1	LCP2	Q13094	510
PRAM1	BRAF	P15056	500

IntAct

86 interactions, top by confidence:

A	B	Type	Score
FXR2	PRAM1	psi-mi:“MI:0915”(physical association)	0.780
PRAM1	FXR2	psi-mi:“MI:0915”(physical association)	0.780
SKAP1	PRAM1	psi-mi:“MI:0915”(physical association)	0.670
PRAM1	SKAP1	psi-mi:“MI:0915”(physical association)	0.670
NEDD9	PRAM1	psi-mi:“MI:0915”(physical association)	0.600
TRIM27	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
CCDC57	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
KRT40	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
ABI2	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
PRAM1	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
PRAM1	KRT40	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
SKAP1	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
FXR1	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
BCAR1	PRAM1	psi-mi:“MI:0915”(physical association)	0.560
TP53BP2	PRAM1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (58): PRAM1 (Two-hybrid), PRAM1 (Two-hybrid), PRAM1 (Two-hybrid), PRAM1 (Two-hybrid), KRT40 (Two-hybrid), CCDC57 (Two-hybrid), PRAM1 (Affinity Capture-MS), PRAM1 (Affinity Capture-MS), PRAM1 (Affinity Capture-MS), PRAM1 (Affinity Capture-MS), PRAM1 (Affinity Capture-Western), PRAM1 (Affinity Capture-Western), PRAM1 (Two-hybrid), PRAM1 (Two-hybrid), PRAM1 (Two-hybrid)

ESM2 similar proteins: A0A8I5ZN27, A6NNT2, D3ZEN0, E1AZ71, E1BM58, O15061, O15446, O55103, O88737, O88778, P08855, P0C671, P10636, P10637, P12036, P16884, P19246, P19332, P27816, P34926, P36225, P53814, P62521, P78559, Q06002, Q09666, Q0VA45, Q28181, Q3TN34, Q3UH66, Q4R729, Q5S6V2, Q5STT6, Q5T0Z8, Q5YCV9, Q5YCW0, Q5YCW1, Q63425, Q76KJ5, Q7Z2K8

Diamond homologs: A2A995, D3ZIE4, O15117, O35601, Q5VWT5, Q6BCL1, Q96QH2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 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.

GO biological processes:

GO term	Partners	Fold	FDR
cell division	5	9.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	118
Likely benign	15
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1129 predictions. Top by Δscore:

Variant	Effect	Δscore
19:8490590:TCA:T	donor_loss	1.0000
19:8490592:A:AC	donor_gain	1.0000
19:8490592:ACAT:A	donor_loss	1.0000
19:8490593:C:CC	donor_gain	1.0000
19:8490593:C:CG	donor_loss	1.0000
19:8490593:CA:C	donor_gain	1.0000
19:8490757:C:CC	acceptor_gain	1.0000
19:8491007:C:CT	acceptor_gain	1.0000
19:8491010:C:CT	acceptor_gain	1.0000
19:8491011:A:T	acceptor_gain	1.0000
19:8498221:A:AC	donor_gain	1.0000
19:8498222:C:CC	donor_gain	1.0000
19:8490371:CC:C	acceptor_gain	0.9900
19:8490372:CC:C	acceptor_gain	0.9900
19:8490474:A:AC	donor_gain	0.9900
19:8490475:C:CC	donor_gain	0.9900
19:8490508:ATC:A	acceptor_loss	0.9900
19:8490509:TC:T	acceptor_loss	0.9900
19:8490510:C:CC	acceptor_gain	0.9900
19:8490587:CACT:C	donor_loss	0.9900
19:8490593:CATT:C	donor_gain	0.9900
19:8490753:CAAA:C	acceptor_gain	0.9900
19:8491007:C:T	acceptor_gain	0.9900
19:8498222:CTG:C	donor_gain	0.9900
19:8499776:CTCTC:C	acceptor_gain	0.9900
19:8499778:CTC:C	acceptor_gain	0.9900
19:8499779:TCCTA:T	acceptor_loss	0.9900
19:8499781:C:CC	acceptor_gain	0.9900
19:8499782:T:G	acceptor_loss	0.9900
19:8490369:CTCC:C	acceptor_gain	0.9800

AlphaMissense

4346 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:8490890:G:C	F580L	1.000
19:8490890:G:T	F580L	1.000
19:8490892:A:G	F580L	1.000
19:8490506:C:T	G637D	0.999
19:8490611:C:G	R630P	0.999
19:8490613:G:C	C629W	0.999
19:8490653:A:G	L616P	0.999
19:8490754:A:C	F582L	0.999
19:8490754:A:T	F582L	0.999
19:8490756:A:G	F582L	0.999
19:8490891:A:G	F580S	0.999
19:8490900:C:G	R577P	0.999
19:8490902:G:C	F576L	0.999
19:8490902:G:T	F576L	0.999
19:8490903:A:G	F576S	0.999
19:8490904:A:G	F576L	0.999
19:8490506:C:A	G637V	0.998
19:8490614:C:T	C629Y	0.998
19:8490615:A:G	C629R	0.998
19:8490617:A:G	L628P	0.998
19:8490617:A:T	L628Q	0.998
19:8490662:C:A	G613V	0.998
19:8490755:A:G	F582S	0.998
19:8490903:A:C	F576C	0.998
19:8490485:A:G	L644P	0.997
19:8490500:A:T	V639E	0.997
19:8490507:C:G	G637R	0.997
19:8490594:A:G	Y636H	0.997
19:8490644:A:T	I619N	0.997
19:8490677:A:G	L608P	0.997

dbSNP variants (sampled 300 via entrez): RS1000149801 (19:8503806 G>T), RS1000176724 (19:8496183 AG>A), RS1000438058 (19:8504118 G>A), RS1000593054 (19:8499499 G>A), RS1000799892 (19:8494273 G>A), RS1001388163 (19:8489987 A>G), RS1001402744 (19:8491727 G>A), RS1001503163 (19:8495394 C>T), RS1001565895 (19:8495289 G>A,T), RS1001598368 (19:8500825 G>A), RS1001797892 (19:8500808 C>G), RS1002309341 (19:8491303 G>A), RS1002501619 (19:8502400 G>A), RS1002617631 (19:8502217 C>T), RS1002634931 (19:8503221 T>A,C)

Disease associations

OMIM: gene MIM:606466 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000175_8	Height	1.000000e-06
GCST005194_131	Coronary artery disease	5.000000e-07
GCST90002379_192	Basophil count	6.000000e-22
GCST90002380_10	Basophil percentage of white cells	6.000000e-28

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases expression, decreases expression, decreases reaction, increases phosphorylation, increases reaction (+1 more)	4
Tretinoin	affects cotreatment, increases expression, decreases expression, decreases reaction	4
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
titanium dioxide	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Am 580	increases expression	1
CGP 52608	affects binding, increases reaction	1
benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone	decreases reaction, increases phosphorylation, increases reaction	1
monomethylarsonous acid	affects cotreatment, increases expression	1
dimethylarsinous acid	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Rosiglitazone	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Air Pollutants	increases abundance, affects expression	1
Cisplatin	decreases expression	1
Hydrogen Peroxide	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1
Smoke	increases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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