SPRYD4

Summary

SPRYD4 (SPRY domain containing 4, HGNC:27468) is a protein-coding gene on chromosome 12q13.3, encoding SPRY domain-containing protein 4 (Q8WW59). It is a selective cancer dependency (DepMap: 26.3% of cell lines).

Located in nucleus.

Source: NCBI Gene 283377 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 28 total
• Cancer dependency (DepMap): dependent in 26.3% of screened cell lines
• MANE Select transcript: NM_207344

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27468
Approved symbol	SPRYD4
Name	SPRY domain containing 4
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp686N0877
Ensembl gene	ENSG00000176422
Ensembl biotype	protein_coding
Entrez	283377

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000338146

RefSeq mRNA: 1 — MANE Select: NM_207344 NM_207344

CCDS: CCDS8920

Canonical transcript exons

ENST00000338146 — 2 exons

Exon	Start	End
ENSE00001268814	56468578	56468676
ENSE00001361143	56469039	56479708

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 86.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9974 / max 197.3283, expressed in 1803 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126111	14.9974	1803

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	86.66	gold quality
right lobe of liver	UBERON:0001114	86.40	gold quality
liver	UBERON:0002107	85.95	gold quality
ileal mucosa	UBERON:0000331	84.31	gold quality
kidney epithelium	UBERON:0004819	83.43	silver quality
pancreatic ductal cell	CL:0002079	82.32	gold quality
deltoid	UBERON:0001476	79.62	silver quality
body of pancreas	UBERON:0001150	76.20	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	75.75	silver quality
esophagus squamous epithelium	UBERON:0006920	75.68	gold quality
quadriceps femoris	UBERON:0001377	75.29	silver quality
biceps brachii	UBERON:0001507	75.07	silver quality
gastrocnemius	UBERON:0001388	74.85	gold quality
cardiac muscle of right atrium	UBERON:0003379	74.61	gold quality
pancreas	UBERON:0001264	74.35	gold quality
islet of Langerhans	UBERON:0000006	74.29	gold quality
muscle of leg	UBERON:0001383	74.27	gold quality
gingival epithelium	UBERON:0001949	74.13	silver quality
right adrenal gland	UBERON:0001233	74.05	gold quality
right adrenal gland cortex	UBERON:0035827	73.88	gold quality
vastus lateralis	UBERON:0001379	73.81	silver quality
mucosa of transverse colon	UBERON:0004991	73.79	gold quality
skeletal muscle tissue	UBERON:0001134	73.78	gold quality
muscle tissue	UBERON:0002385	73.57	gold quality
left adrenal gland	UBERON:0001234	73.47	gold quality
left adrenal gland cortex	UBERON:0035825	73.23	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.87	gold quality
cerebellar hemisphere	UBERON:0002245	72.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	72.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

93 targeting SPRYD4, 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-12118	100.00	65.88	1270
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-185-3P	99.95	67.01	1743

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 26.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• Subcellular localization demonstrates that SPRYD4 (SPRY-domain-containing) protein is localized in the nucleus when overexpressed in COS-7 green monkey cells. (PMID:17852359)
• SPRYD4 expression may serve as a biomarker for a good overall and relapse-free survival in hepatocellular carcinoma patients. (PMID:30238408)
• MicroRNA-363-3p promote the development of acute myeloid leukemia with RUNX1 mutation by targeting SPRYD4 and FNDC3B. (PMID:33950983)
• Identification of SPRYD4 as a tumour suppressor predicts prognosis and correlates with immune infiltration in cholangiocarcinoma. (PMID:37142983)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	spryd4	ENSDARG00000023309
mus_musculus	Spryd4	ENSMUSG00000051346
rattus_norvegicus	Spryd4	ENSRNOG00000003127

Paralogs (12): CD86 (ENSG00000114013), CD274 (ENSG00000120217), CD80 (ENSG00000121594), RFPL1 (ENSG00000128250), RFPL2 (ENSG00000128253), RFPL3 (ENSG00000128276), RNF152 (ENSG00000176641), RNF135 (ENSG00000181481), PDCD1LG2 (ENSG00000197646), RFPL4A (ENSG00000223638), RFPL4AL1 (ENSG00000229292), RFPL4B (ENSG00000251258)

Protein

Protein identifiers

SPRY domain-containing protein 4 — Q8WW59 (reviewed: Q8WW59)

All UniProt accessions (1): Q8WW59

RefSeq proteins (1): NP_997227* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR050617	E3_ligase_FN3/SPRY	Family

Pfam: PF00622

UniProt features (6 total): modified residue 3, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WW59-F1	88.63	0.80

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 (3): 53, 130, 139

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 118 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, NUYTTEN_EZH2_TARGETS_DN, KRIGE_RESPONSE_TO_TOSEDOSTAT_6HR_DN, MARTENS_TRETINOIN_RESPONSE_DN, BRUINS_UVC_RESPONSE_MIDDLE, RATTENBACHER_BOUND_BY_CELF1, FOSTER_KDM1A_TARGETS_DN, ARID5B_TARGET_GENES, BARX1_TARGET_GENES, E2F2_TARGET_GENES, FOXG1_TARGET_GENES, GLI3_TARGET_GENES, HES4_TARGET_GENES, KAT5_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
binding	1
cytoplasm	1

Protein interactions and networks

STRING

698 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRYD4	SMCO3	A2RU48	539
SPRYD4	C12orf71	A8MTZ7	527
SPRYD4	MIP	P30301	461
SPRYD4	GLS2	Q9UI32	455
SPRYD4	LYZL6	O75951	443
SPRYD4	GTPBP8	Q8N3Z3	439
SPRYD4	LYZL4	Q96KX0	433
SPRYD4	ANKRD46	Q86W74	428
SPRYD4	SPPL2B	Q8TCT7	427
SPRYD4	TMEM62	Q0P6H9	403
SPRYD4	ZNF391	Q9UJN7	399
SPRYD4	CCNT1	O60563	398
SPRYD4	CPPED1	Q9BRF8	392
SPRYD4	SPRYD7	Q5W111	389
SPRYD4	LYSMD3	Q7Z3D4	378
SPRYD4	CPM	P14384	378

IntAct

33 interactions, top by confidence:

A	B	Type	Score
SPG11	AP5Z1	psi-mi:“MI:0914”(association)	0.620
COQ5	COQ9	psi-mi:“MI:0914”(association)	0.590
EEF1B2	SPRYD4	psi-mi:“MI:0915”(physical association)	0.560
CCL5	C4A	psi-mi:“MI:0914”(association)	0.530
SPRYD4	ATP5MG	psi-mi:“MI:0915”(physical association)	0.500
SPRYD4	ATP5MG	psi-mi:“MI:0914”(association)	0.500
SPRYD4	OXCT1	psi-mi:“MI:0915”(physical association)	0.400
GRB2	SPRYD4	psi-mi:“MI:0915”(physical association)	0.400
Ambra1	SPRYD4	psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
SPRYD4	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
SPRYD4	CDC34	psi-mi:“MI:0914”(association)	0.350
COL10A1	PLOD2	psi-mi:“MI:0914”(association)	0.350
CIART	UQCRQ	psi-mi:“MI:0914”(association)	0.350
FMNL2	PLPBP	psi-mi:“MI:0914”(association)	0.350
NUDT13	PLPBP	psi-mi:“MI:0914”(association)	0.350
HOXD3	GM2A	psi-mi:“MI:0914”(association)	0.350
PTPN2	COIL	psi-mi:“MI:0914”(association)	0.350
ZNG1A	ADK	psi-mi:“MI:0914”(association)	0.350
ZDHHC21	SPRYD4	psi-mi:“MI:0914”(association)	0.350
DCAF10	BAG2	psi-mi:“MI:0914”(association)	0.350
GOLGA2	FTL	psi-mi:“MI:0914”(association)	0.350
SLC18B1	AP3D1	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
HSPD1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
MGST3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
PDK1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
TRMT61B	VWA8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (52): SPRYD4 (Affinity Capture-RNA), SPRYD4 (Affinity Capture-RNA), SPRYD4 (Affinity Capture-MS), SPRYD4 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), IDE (Affinity Capture-MS), GPI (Affinity Capture-MS), PMPCB (Affinity Capture-MS), PMPCA (Affinity Capture-MS), SPRYD4 (Affinity Capture-MS), ECH1 (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), USMG5 (Affinity Capture-MS), ATP5I (Affinity Capture-MS), ATP5C1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JXN2, A1L4K1, A2AAX3, D3ZA50, G3X9X1, O15344, O15519, O70583, P0C2W1, P42575, P82457, P82458, Q1LY10, Q2TBA0, Q2TBA3, Q4FZT8, Q568M3, Q5RD56, Q5RDY3, Q5W0U4, Q5ZJU2, Q6DEL7, Q6NZ03, Q6P6S3, Q6VVB1, Q7TNM2, Q7Z4K8, Q7Z6J4, Q7ZUM8, Q7ZX59, Q80V85, Q80WG7, Q8AYC9, Q8BY35, Q8BYN5, Q8BZ52, Q8IY47, Q8K3B1, Q8WW59, Q91WK1

Diamond homologs: A0A2P1BRP3, A0A2P1BRQ0, A0ZSK3, A0ZSK4, O95361, Q14142, Q14258, Q1LY10, Q1XHU0, Q309B1, Q4FZT8, Q5R760, Q61510, Q6MFZ5, Q6P6S3, Q80YW5, Q8BVW3, Q8WV44, Q8WW59, Q91453, Q91WK1, Q98989, Q98993, Q99PP9, Q9ESN2, Q9HCM9, A0A3B3IT33, A0JN74, A4QPC6, A6NCK2, A6NDI0, A6NGJ6, A6NI03, A6NLI5, B0BLU1, B1H278, C9J1S8, D3YY23, I1YAP6, O00478

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 40 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
Mitochondrial protein degradation	5	19.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2389 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56471639:CCCAC:C	acceptor_gain	1.0000
12:56471640:CCAC:C	acceptor_gain	1.0000
12:56471640:CCACC:C	acceptor_gain	1.0000
12:56471641:CAC:C	acceptor_gain	1.0000
12:56471641:CACC:C	acceptor_gain	1.0000
12:56471644:CTG:C	acceptor_loss	1.0000
12:56472106:AAC:A	donor_gain	1.0000
12:56473321:C:CC	acceptor_gain	1.0000
12:56473327:T:C	acceptor_gain	1.0000
12:56473327:T:TC	acceptor_gain	1.0000
12:56473459:TCACC:T	donor_loss	1.0000
12:56473460:CA:C	donor_loss	1.0000
12:56473461:A:AC	donor_gain	1.0000
12:56473462:C:CC	donor_gain	1.0000
12:56473462:CCTGG:C	donor_gain	1.0000
12:56474542:A:AC	donor_gain	1.0000
12:56474543:C:CC	donor_gain	1.0000
12:56474716:CACAG:C	acceptor_gain	1.0000
12:56474717:ACAG:A	acceptor_gain	1.0000
12:56474718:CAG:C	acceptor_gain	1.0000
12:56474718:CAGC:C	acceptor_gain	1.0000
12:56474719:AG:A	acceptor_gain	1.0000
12:56474720:GC:G	acceptor_loss	1.0000
12:56474721:C:CC	acceptor_gain	1.0000
12:56474723:A:C	acceptor_gain	1.0000
12:56474840:TCTTA:T	donor_loss	1.0000
12:56474841:CTTA:C	donor_loss	1.0000
12:56474842:TTAC:T	donor_loss	1.0000
12:56474843:TACC:T	donor_loss	1.0000
12:56474895:CA:C	acceptor_gain	1.0000

AlphaMissense

1327 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56469164:T:C	F71L	0.996
12:56469166:C:A	F71L	0.996
12:56469166:C:G	F71L	0.996
12:56469251:T:C	F100L	0.996
12:56469253:C:A	F100L	0.996
12:56469253:C:G	F100L	0.996
12:56469255:G:C	R101P	0.995
12:56469221:T:A	W90R	0.993
12:56469221:T:C	W90R	0.993
12:56469344:T:A	W131R	0.993
12:56469344:T:C	W131R	0.993
12:56469261:G:A	G103E	0.992
12:56469223:G:C	W90C	0.990
12:56469223:G:T	W90C	0.990
12:56469516:T:C	F188S	0.988
12:56469266:G:C	A105P	0.987
12:56469524:T:A	W191R	0.987
12:56469524:T:C	W191R	0.987
12:56469165:T:C	F71S	0.986
12:56469252:T:C	F100S	0.985
12:56469047:T:C	F32L	0.984
12:56469049:C:A	F32L	0.984
12:56469049:C:G	F32L	0.984
12:56469300:G:A	G116D	0.983
12:56469526:G:C	W191C	0.983
12:56469526:G:T	W191C	0.983
12:56469324:T:C	F124S	0.982
12:56469164:T:A	F71I	0.981
12:56469189:C:A	A79E	0.981
12:56469346:G:C	W131C	0.981

dbSNP variants (sampled 300 via entrez): RS1000094799 (12:56475547 C>A,G,T), RS1000265411 (12:56472948 C>A,T), RS1000318992 (12:56472557 A>C,G), RS1000499834 (12:56467813 T>C), RS1001112067 (12:56467471 C>G,T), RS1001899251 (12:56466944 C>T), RS1002101084 (12:56478956 C>A,G), RS1002353130 (12:56467178 A>C), RS1002486141 (12:56473853 C>T), RS1003058209 (12:56477533 C>T), RS1003111852 (12:56467164 G>A,T), RS1003160316 (12:56470645 A>C), RS1003394894 (12:56473917 GATAA>G), RS1003912779 (12:56466623 A>G), RS1003966532 (12:56466926 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001639_2	Metabolite levels	7.000000e-30
GCST002115_16	Axial length	4.000000e-07
GCST006249_86	Serum metabolite levels	3.000000e-13
GCST007382_10	Plasma free amino acid levels (adjusted for twenty other PFAAs)	2.000000e-18
GCST007385_2	Plasma free amino acid levels	1.000000e-10
GCST008062_68	Blood urea nitrogen levels	1.000000e-15
GCST012232_21	Lipoprotein (a) levels	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0005318	axial length measurement
EFO:0005134	amino acid measurement
EFO:0009768	glutamine measurement
EFO:0006925	lipoprotein A measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
GSK-J4	decreases expression	1
bisphenol A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
bisphenol B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ozone	affects expression, increases abundance	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases methylation	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TQ27	HAP1 SPRYD4 (-) 1	Cancer cell line	Male
CVCL_XT81	HAP1 SPRYD4 (-) 2	Cancer cell line	Male
CVCL_XT82	HAP1 SPRYD4 (-) 3	Cancer cell line	Male
CVCL_XT83	HAP1 SPRYD4 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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