SPDEF

Summary

SPDEF (SAM pointed domain containing ETS transcription factor, HGNC:17257) is a protein-coding gene on chromosome 6p21.31, encoding SAM pointed domain-containing Ets transcription factor (O95238). May function as an androgen-independent transactivator of the prostate-specific antigen (PSA) promoter.

The protein encoded by this gene belongs to the ETS family of transcription factors. It is highly expressed in the prostate epithelial cells, and functions as an androgen-independent transactivator of prostate-specific antigen (PSA) promoter. Higher expression of this protein has also been reported in brain, breast, lung and ovarian tumors, compared to the corresponding normal tissues, and it shows better tumor-association than other cancer-associated molecules, making it a more suitable target for developing specific cancer therapies. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 25803 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 61 total
• Transcription factor: yes — 27 downstream targets (CollecTRI)
• MANE Select transcript: NM_012391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17257
Approved symbol	SPDEF
Name	SAM pointed domain containing ETS transcription factor
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Aliases	PDEF, bA375E1.3
Ensembl gene	ENSG00000124664
Ensembl biotype	protein_coding
OMIM	608144
Entrez	25803

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000374037, ENST00000544425, ENST00000886645, ENST00000886647, ENST00000938449, ENST00000943125, ENST00000943126, ENST00000943127

RefSeq mRNA: 2 — MANE Select: NM_012391 NM_001252294, NM_012391

CCDS: CCDS4794, CCDS59013

Canonical transcript exons

ENST00000374037 — 6 exons

Exon	Start	End
ENSE00000849545	34539515	34539562
ENSE00000849546	34540984	34541181
ENSE00001308802	34555929	34556329
ENSE00001311158	34539250	34539396
ENSE00001462215	34537802	34538452
ENSE00001462227	34544020	34544484

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 95.81.

FANTOM5 (CAGE): breadth broad, TPM avg 13.7837 / max 909.9582, expressed in 239 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73254	12.3738	210
73253	0.9899	182
73252	0.3926	138
73251	0.0274	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	95.81	gold quality
nasal cavity epithelium	UBERON:0005384	95.25	gold quality
mucosa of transverse colon	UBERON:0004991	92.81	gold quality
prostate gland	UBERON:0002367	92.27	gold quality
ileal mucosa	UBERON:0000331	91.59	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.81	gold quality
buccal mucosa cell	CL:0002336	89.66	silver quality
nasal cavity mucosa	UBERON:0001826	88.78	gold quality
saliva-secreting gland	UBERON:0001044	88.49	gold quality
trachea	UBERON:0003126	87.90	gold quality
gluteal muscle	UBERON:0002000	87.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.08	gold quality
mammary duct	UBERON:0001765	86.95	gold quality
minor salivary gland	UBERON:0001830	86.63	gold quality
epithelium of mammary gland	UBERON:0003244	86.63	gold quality
palpebral conjunctiva	UBERON:0001812	86.52	gold quality
colonic mucosa	UBERON:0000317	86.46	gold quality
vastus lateralis	UBERON:0001379	86.01	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.59	silver quality
quadriceps femoris	UBERON:0001377	85.19	gold quality
tendon of biceps brachii	UBERON:0008188	84.78	silver quality
diaphragm	UBERON:0001103	84.55	gold quality
mouth mucosa	UBERON:0003729	83.90	gold quality
bronchus	UBERON:0002185	83.80	gold quality
epithelium of bronchus	UBERON:0002031	83.79	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	82.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	82.56	gold quality
right uterine tube	UBERON:0001302	81.95	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.29	silver quality
bronchial epithelial cell	CL:0002328	81.28	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	47.42
E-CURD-114	yes	46.49
E-GEOD-125970	yes	23.69
E-MTAB-8410	yes	12.89
E-HCAD-1	yes	8.79
E-ANND-3	yes	4.44

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

27 targets.

Target	Regulation
AGR2	Activation
BIRC5	Repression
CD74
CDH1	Activation
CDH17
CDKN1A	Unknown
CDKN2A
CSF1R
ERBB2
ERVK-11
ERVW-4
KLK3	Unknown
MMP13	Repression
MMP9	Repression
MUC2	Activation
PLAU	Unknown
PLAUR	Repression
PLG
RNU1-1
RNU2-1
RNU6-1	Repression
SERPINB5	Activation
SPDEF
SPINK4	Activation
SQSTM1	Activation
STMN1
TNFRSF11A

JASPAR motifs

Motif	Name	Family
MA0686.1	SPDEF	Ets-related
MA0686.2	SPDEF	Ets-related

JASPAR matrix evidence (PMIDs): PMID:23449978

Upstream regulators (CollecTRI, top): AR, KDM5B, NKX3-1, NWD1, SPDEF, STAT6

miRNA regulators (miRDB)

21 targeting SPDEF, 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-6798-5P	100.00	65.77	699
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-6872-3P	97.08	66.99	750
HSA-MIR-2861	95.24	65.47	1056

Literature-anchored findings (GeneRIF, showing 40)

• NKX-3.1 interacts with prostate-derived Ets factor and regulates the activity of the PSA promoter. (PMID:11809674)
• PDEF upregulates p62 promoter activity at 2 sites. PSI downregulates PDEF-induced p62 promoter activation through one of these sites. (PMID:12700667)
• Pdef loss may alter the expression of genes controlling progression to invasive breast cancer. (PMID:12907642)
• identified novel protein-protein interaction domains within NKX-3.1 and PDEF that operate in concert with their respective DNA binding domains to mediate functional interactions between these growth regulatory transcription factors (PMID:15523673)
• Despite common essential features that are shared among Ets members, the crystal structure of PDEF Ets domain demonstrates distinct patterns of interactions at different positions of DNA in achieving sequence specific recognition. (PMID:15882048)
• RUNX factors participate in prostate epithelial cell function and cooperate with an Ets transcription factor to regulate PSA gene expression (PMID:16237704)
• PDEF overexpression is associated with activation of ErbB2 and CSF-1R and breast tumor progression (PMID:16357167)
• prostate-derived Ets factor is a potential marker and target in ovarian cancer (PMID:17197890)
• SPDEF was induced following intratracheal allergen exposure and after Th2 cytokine stimulation and was sufficient to cause goblet cell differentiation of Clara cells in vivo. (PMID:17347682)
• these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression. (PMID:17521701)
• PDEF mRNA expression could be useful in breast cancer molecular staging. (PMID:17971898)
• increased PDEF expression along with reduced survivin was associated with prolonged survival of patients with ovarian cancer (PMID:18567002)
• analysis of PDEF transcriptional networks regulating cell migration during cancer progression (PMID:18579687)
• prostate derived Ets factor mRNA quantitation did not reveal any significant differences between breast cancer patients and healthy women (PMID:18846421)
• PDEF may be regulated by Erbb2 or EGFR-activated signaling pathways in breast cancer cells. (PMID:19203193)
• we hypothesize that SPDEF has a function in the specification of the progenitor cells of the luminal epithelial lineage that become targets of oncogenesis in luminal breast cancer. (PMID:19505923)
• Spdef was sufficient to inhibit proliferation of intestinal progenitors and induce differentiation into goblet cells. (PMID:19786015)
• PDEF is a negative regulator of colon cancer cell growth and migration. (PMID:19830706)
• Transcriptional regulation of p21/CIP1 cell cycle inhibitor by PDEF controls cell proliferation and mammary tumor progression (PMID:20139077)
• results show that SPDEF plays a critical role in regulating a transcriptional network mediating IL-13-induced MUC5AC synthesis dependent on STAT6 (PMID:21275604)
• PDEF is a negative regulator of prostate tumor progression and the miR-204-PDEF regulatory axis contributes to PDEF protein loss and resultant cancer progression. (PMID:21446014)
• Up-regulation of PDEF is associated with a favorable prognosis in patients with clinically localized prostate cancer. (PMID:21656828)
• Studies indicate that PDEF is a negative regulator of tumor progression and metastasis. (PMID:21764212)
• PDEF may inhibit prostate cancer progression by transcriptional downregulation of oncogenic STMN expression. (PMID:22378487)
• SPDEF functions as a tumor metastasis suppressor in vivo. (PMID:22761428)
• Data show that SAM pointed domain ETS factor (SPDEF) was induced by rhinoviral infection of primary human airway cells. (PMID:23012424)
• In colorectal tumors from patients, loss of SPDEF was observed in approximately 85% of tumors and correlated with progression from normal tissue, to adenoma, to adenocarcinoma. (PMID:23376423)
• these findings show that PDEF-CEACAM6 is a highly active oncogenic axis in breast cancer (PMID:23592399)
• Data demonstrate that SPDEF is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. (PMID:23665202)
• Data indicate that Il-9 and IL-13 regulate expressions of MUC5AC, SPDEF and matrix metalloproteinase 7 (MMP-7) in pediatric bronchial epithelial cell. (PMID:23671562)
• Prostate-derived ETS factor (PDEF) is identified as a mediator of mammary luminal epithelial lineage-specific gene expression and as a factor required for tumorigenesis in a subset of breast cancers. (PMID:23764000)
• PDEF undergoes DNA methylation in breast cancer cells. (PMID:23921628)
• Host Kruppel-like factor 15, Slug, and SPDEF, stimulated the herpes simplex virus type 1 ICP0 promoter more than 150-fold. (PMID:24027338)
• we identified four proteins with different expression in paclitaxel resistant cells, i.e., serpin B3, serpin B4, heat shock protein 27 (all three upregulated) and cytokeratin 18 (downregulated). (PMID:24898171)
• SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene. (PMID:25254494)
• We found significantly increased SPDEF and MUC5AC expression in CRSwNP patients compared to the controls (P < .05); the mRNA level of SPDEF was positively correlated with MUC5AC expression in CRS patients (P < .05). (PMID:25376946)
• PDEF gene expression is associated with the extent of bladder neoplasia and PDEF modulated the expressions of EMT-related genes. (PMID:26965996)
• miR-125b inhibits SPDEF expression modulating goblet cell differentiation and mucus secretion in asthma (PMID:27112664)
• PDEF regulates many genes, which participate in various stages of tumor development. (PMID:27612480)
• These results indicate efficient SPDEF silencing and downregulation of mucus-related gene expression by epigenetic editing, in human lung epithelial cells. (PMID:28011616)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	SPDEF	ENSDARG00000029930
mus_musculus	Spdef	ENSMUSG00000024215
rattus_norvegicus	Spdef	ENSRNOG00000000491
drosophila_melanogaster	Ets98B	FBGN0005659
caenorhabditis_elegans		WBGENE00017687

Paralogs (28): ETV1 (ENSG00000006468), ETV7 (ENSG00000010030), SPI1 (ENSG00000066336), ELF4 (ENSG00000102034), ETV2 (ENSG00000105672), ERF (ENSG00000105722), ELF2 (ENSG00000109381), ELK3 (ENSG00000111145), ETV3 (ENSG00000117036), ELF1 (ENSG00000120690), ELK1 (ENSG00000126767), ETS1 (ENSG00000134954), EHF (ENSG00000135373), ELF5 (ENSG00000135374), ETV6 (ENSG00000139083), FLI1 (ENSG00000151702), GABPA (ENSG00000154727), ERG (ENSG00000157554), ETS2 (ENSG00000157557), ELK4 (ENSG00000158711), ELF3 (ENSG00000163435), FEV (ENSG00000163497), SPIC (ENSG00000166211), ETV4 (ENSG00000175832), ETV5 (ENSG00000244405), ETV3L (ENSG00000253831), ERFL (ENSG00000268041), SPIB (ENSG00000269404)

Protein

Protein identifiers

SAM pointed domain-containing Ets transcription factor — O95238 (reviewed: O95238)

Alternative names: Prostate epithelium-specific Ets transcription factor, Prostate-derived Ets factor

All UniProt accessions (1): O95238

UniProt curated annotations — full annotation on UniProt →

Function. May function as an androgen-independent transactivator of the prostate-specific antigen (PSA) promoter. Binds to 5’-GGAT-3’ DNA sequences. May play a role in the regulation of the prostate gland and/or prostate cancer development. Acts as a transcriptional activator for SERPINB5 promoter.

Subunit / interactions. Interacts with the DNA-binding domain of the androgen receptor. Interacts with NKX3-1.

Subcellular location. Nucleus.

Tissue specificity. Expressed in a very restricted set of primarily hormone-regulated epithelial tissues with particularly high expression in the prostate gland. Significantly lower expression is seen in other hormone regulated tissues such as mammary gland, salivary gland, and ovary. Expressed in prostate carcinoma cells.

Similarity. Belongs to the ETS family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95238-1	1	yes
O95238-2	2

RefSeq proteins (2): NP_001239223, NP_036523* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000418	Ets_dom	Domain
IPR003118	Pointed_dom	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR046328	ETS_fam	Family

Pfam: PF00178, PF02198

UniProt features (30 total): helix 11, strand 5, turn 4, region of interest 2, sequence conflict 2, chain 1, domain 1, DNA-binding region 1, compositionally biased region 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1YO5	X-RAY DIFFRACTION	2
2DKX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95238-F1	70.82	0.50

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 137 (showing top): ELVIDGE_HYPOXIA_DN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, HNF3ALPHA_Q6, GOBP_POSITIVE_REGULATION_OF_CELL_FATE_COMMITMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_LUNG_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, HALMOS_CEBPA_TARGETS_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, AREB6_01, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, FREAC3_01, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), glandular epithelial cell development (GO:0002068), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), negative regulation of cell fate commitment (GO:0010454), positive regulation of cell fate commitment (GO:0010455), cell differentiation (GO:0030154), positive regulation of apoptotic process (GO:0043065), positive regulation of transcription by RNA polymerase II (GO:0045944), lung goblet cell differentiation (GO:0060480), intestinal epithelial cell development (GO:0060576), epithelial cell fate commitment (GO:0072148), regulation of DNA-templated transcription (GO:0006355), cell fate commitment (GO:0045165)

GO Molecular Function (6): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
cell fate commitment	3
columnar/cuboidal epithelial cell development	2
regulation of DNA-templated transcription	2
DNA-templated transcription	2
regulation of cell fate commitment	2
cellular developmental process	2
negative regulation of DNA-templated transcription	1
glandular epithelial cell differentiation	1
negative regulation of cell differentiation	1
positive regulation of cell differentiation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
positive regulation of DNA-templated transcription	1
lobar bronchus epithelium development	1
lung secretory cell differentiation	1
intestinal epithelial cell differentiation	1
epithelial cell differentiation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell differentiation	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1166 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPDEF	NKX2-1	P43699	850
SPDEF	STAT6	P42226	786
SPDEF	NKX3-1	Q99801	779
SPDEF	IL13	P35225	693
SPDEF	AGR2	O95994	665
SPDEF	MUC5AC	P98088	663
SPDEF	FOXA3	P55318	636
SPDEF	ATOH1	Q92858	630
SPDEF	AR	P10275	624
SPDEF	MUC5B	Q9HC84	592
SPDEF	KLF4	P78338	586
SPDEF	FOXA1	P55317	584
SPDEF	CDH1	P12830	527
SPDEF	FOXA2	Q9Y261	526
SPDEF	SCGB1A1	P11684	521

IntAct

31 interactions, top by confidence:

A	B	Type	Score
SPDEF	PSMA1	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	TTC23	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	CEP57	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	FAM161B	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	SNX20	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	COX5A	psi-mi:“MI:0915”(physical association)	0.560
BRK1	SPDEF	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	IMMP2L	psi-mi:“MI:0915”(physical association)	0.400
SPDEF	STX16	psi-mi:“MI:0915”(physical association)	0.400
PCGF2	SPDEF	psi-mi:“MI:0915”(physical association)	0.370
SPDEF	SLC4A2	psi-mi:“MI:0914”(association)	0.350
SPDEF	UNC119B	psi-mi:“MI:0914”(association)	0.350
PSMA1	SPDEF	psi-mi:“MI:0915”(physical association)	0.000
TTC23	SPDEF	psi-mi:“MI:0915”(physical association)	0.000
SNX20	SPDEF	psi-mi:“MI:0915”(physical association)	0.000
COX5A	SPDEF	psi-mi:“MI:0915”(physical association)	0.000
CEP57	SPDEF	psi-mi:“MI:0915”(physical association)	0.000
ENKD1	SPDEF	psi-mi:“MI:0915”(physical association)	0.000
FAM161B	SPDEF	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (57): SPDEF (Two-hybrid), UNC119 (Affinity Capture-MS), PRDM16 (Affinity Capture-MS), MECOM (Affinity Capture-MS), MYO5C (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC30A9 (Affinity Capture-MS), FASTKD1 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), SPDEF (Biochemical Activity), PRDM16 (Affinity Capture-MS), MECOM (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), MYO5C (Affinity Capture-MS), FASTKD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PPF3, A0A3B3IT52, E9Q3T6, O02747, O13161, O42173, O57374, O73622, O95238, P01103, P01104, P09632, P0C7M4, P10242, P14837, P17278, P30561, P31538, P41738, P46200, Q1KKS8, Q28G02, Q32NH9, Q4JM65, Q5REX1, Q5WM45, Q66IG8, Q68EH7, Q6U8D7, Q6ZTZ1, Q7T1K4, Q8BIL2, Q8BKE5, Q8CFH6, Q8IWB6, Q8JIT7, Q8NHV9, Q8R4S2, Q8R4S4, Q8R4S5

Diamond homologs: A0A1W2PQ73, A0JN51, A1A4L6, A1YF15, A1YG61, A1YG91, A2D4Z7, A2T737, A2T762, A3FEM2, A4GTP4, A8WFJ9, O00321, O01519, O70132, O70273, O95238, P01105, P10157, P11308, P11536, P13474, P14921, P15036, P15037, P15062, P18755, P18756, P19102, P19419, P20105, P26323, P27577, P28322, P28324, P29773, P29774, P29775, P29776, P32519

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
SPDEF	“down-regulates quantity by repression”	MMP9	“transcriptional regulation”
SPDEF	“down-regulates quantity by repression”	MMP13	“transcriptional regulation”
CDK11A	“down-regulates quantity by destabilization”	SPDEF	phosphorylation
CyclinD3/CDK11A	“down-regulates quantity by destabilization”	SPDEF	phosphorylation
CyclinD3/CDK11B	“down-regulates quantity by destabilization”	SPDEF	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

810 predictions. Top by Δscore:

Variant	Effect	Δscore
6:34538450:TGC:T	acceptor_gain	1.0000
6:34538452:CCT:C	acceptor_loss	1.0000
6:34539248:AC:A	donor_gain	1.0000
6:34539249:CC:C	donor_gain	1.0000
6:34539249:CCCTT:C	donor_gain	1.0000
6:34539287:G:C	donor_gain	1.0000
6:34539392:CGAGG:C	acceptor_gain	1.0000
6:34539393:GAGG:G	acceptor_gain	1.0000
6:34539394:AGG:A	acceptor_gain	1.0000
6:34539395:GG:G	acceptor_gain	1.0000
6:34539395:GGC:G	acceptor_loss	1.0000
6:34539396:GCT:G	acceptor_loss	1.0000
6:34539397:C:CC	acceptor_gain	1.0000
6:34539397:CT:C	acceptor_loss	1.0000
6:34539406:C:CT	acceptor_gain	1.0000
6:34539406:C:T	acceptor_gain	1.0000
6:34539407:A:T	acceptor_gain	1.0000
6:34540980:CTACC:C	donor_loss	1.0000
6:34540981:TACC:T	donor_loss	1.0000
6:34540982:ACCT:A	donor_loss	1.0000
6:34540983:CCTGA:C	donor_gain	1.0000
6:34540990:T:TA	donor_gain	1.0000
6:34541181:TCTG:T	acceptor_loss	1.0000
6:34544015:CTCA:C	donor_loss	1.0000
6:34544018:A:AC	donor_gain	1.0000
6:34544018:ACC:A	donor_loss	1.0000
6:34544019:C:CC	donor_gain	1.0000
6:34544019:CCTG:C	donor_gain	1.0000
6:34538448:GATGC:G	acceptor_gain	0.9900
6:34538453:C:CC	acceptor_gain	0.9900

AlphaMissense

2192 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:34538289:G:C	F331L	1.000
6:34538289:G:T	F331L	1.000
6:34538290:A:C	F331C	1.000
6:34538290:A:G	F331S	1.000
6:34538291:A:G	F331L	1.000
6:34538293:T:G	Q330P	1.000
6:34538297:A:C	Y329D	1.000
6:34538297:A:G	Y329H	1.000
6:34538297:A:T	Y329N	1.000
6:34538299:A:T	V328D	1.000
6:34538302:A:G	L327P	1.000
6:34538306:G:T	R326S	1.000
6:34538322:C:A	K320N	1.000
6:34538322:C:G	K320N	1.000
6:34538324:T:C	K320E	1.000
6:34538329:A:T	I318N	1.000
6:34538345:A:C	Y313D	1.000
6:34538345:A:G	Y313H	1.000
6:34538347:T:C	Y312C	1.000
6:34538348:A:G	Y312H	1.000
6:34538354:G:C	R310G	1.000
6:34538354:G:T	R310S	1.000
6:34538356:A:C	I309S	1.000
6:34538356:A:T	I309N	1.000
6:34538359:G:A	S308F	1.000
6:34538360:A:G	S308P	1.000
6:34538362:C:G	R307P	1.000
6:34538363:G:A	R307C	1.000
6:34538363:G:C	R307G	1.000
6:34538363:G:T	R307S	1.000

dbSNP variants (sampled 300 via entrez): RS1000035273 (6:34539150 C>G,T), RS1000234146 (6:34550326 G>A,C), RS1000387922 (6:34539008 A>G), RS1000473559 (6:34555130 ACACG>A), RS1000653997 (6:34544620 G>C), RS1000716277 (6:34555133 C>T), RS1000839538 (6:34555329 CCA>C), RS1001272307 (6:34538674 G>A,T), RS1001485503 (6:34539734 C>T), RS1001697937 (6:34549672 G>A,T), RS1001727113 (6:34550824 G>A), RS1001759834 (6:34550617 G>C), RS1001760554 (6:34544564 G>C,T), RS1001912109 (6:34556166 C>T), RS1002093263 (6:34554413 G>A,C)

Disease associations

OMIM: gene MIM:608144 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003602_15	Inflammatory bowel disease	1.000000e-07
GCST007294_103	Body fat distribution (trunk fat ratio)	3.000000e-11
GCST007295_123	Body fat distribution (leg fat ratio)	1.000000e-12
GCST008152_102	Weight	4.000000e-06
GCST008163_141	Height	8.000000e-06
GCST008163_282	Height	1.000000e-06
GCST010002_50	Refractive error	4.000000e-34
GCST012155_2	Chronic lymphocytic leukemia (time to first treatment)	5.000000e-08
GCST012227_946	Hip circumference adjusted for BMI	2.000000e-08
GCST012227_949	Hip circumference adjusted for BMI	4.000000e-12
GCST012227_950	Hip circumference adjusted for BMI	3.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004338	body weight
EFO:0004920	progression free survival
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Smoke	affects reaction, increases expression, increases abundance	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
methylselenic acid	increases expression	1
titanium dioxide	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
octa-2,4,6-trienoic acid	decreases expression	1
fidarestat	decreases reaction, increases expression	1
seocalcitol	increases expression	1
tebuconazole	decreases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
pyrimidifen	decreases expression	1
thifluzamide	decreases expression	1
abrine	decreases expression	1
pyrachlostrobin	decreases expression	1
LG 100815	decreases expression	1
picoxystrobin	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	increases abundance, increases expression	1

Clinical trials (associated diseases)

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