PSAP

Summary

PSAP (prosaposin, HGNC:9498) is a protein-coding gene on chromosome 10q22.1, encoding Prosaposin (P07602). Saposins are specific low-molecular mass non-enzymatic glycoproteins that act as activator proteins for lysosomal sphingolipid-degrading enzymes, facilitating the hydrolysis of sphingolipids by extracting lipid substrates from membranes and presenting them to their respective en….

This gene encodes a highly conserved preproprotein that is proteolytically processed to generate four main cleavage products including saposins A, B, C, and D. Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities. Mutations in this gene have been associated with Gaucher disease and metachromatic leukodystrophy. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 5660 — RefSeq curated summary.

At a glance

• Gene–disease (curated): metachromatic leukodystrophy due to saposin B deficiency (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 1,021 total — 43 pathogenic, 48 likely-pathogenic (top 3% of genes corpus-wide)
• GTEx eGene: eQTL in 23 tissues, sQTL in 14 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.95 (loss-of-function intolerant), LOEUF 0.51 (moderately constrained)
• MANE Select transcript: NM_002778

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9498
Approved symbol	PSAP
Name	prosaposin
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197746
Ensembl biotype	protein_coding
OMIM	176801
Entrez	5660

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 42 protein_coding, 11 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000394936

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

ENST00000394936, ENST00000493143, ENST00000495196, ENST00000633965, ENST00000870500, ENST00000870501, ENST00000870502, ENST00000870503, ENST00000870504, ENST00000870505, ENST00000870506, ENST00000870507, ENST00000870508, ENST00000870509, ENST00000870510, ENST00000870511, ENST00000870512, ENST00000870513, ENST00000870514, ENST00000870515, ENST00000870516, ENST00000870517, ENST00000870518, ENST00000870519, ENST00000931476, ENST00000931477, ENST00000931478, ENST00000931479, ENST00000931480, ENST00000931481, ENST00000931482, ENST00000931483, ENST00000958165, ENST00000958166, ENST00000958167, ENST00000958168, ENST00000958169, ENST00000958170, ENST00000958171, ENST00000979766, ENST00000979767, ENST00000979769, ENST00000979770, ENST00000979771, ENST00000979773, ENST00000979775, ENST00001025990, ENST00001025991, ENST00001025993, ENST00001025994, ENST00001025997, ENST00001026000, ENST00001069277, ENST00001069278, ENST00001140798

RefSeq mRNA: 3 — MANE Select: NM_002778 NM_001042465, NM_001042466, NM_002778

CCDS: CCDS7311

Canonical transcript exons

ENST00000394936 — 14 exons

Exon	Start	End
ENSE00000987088	71831126	71831251
ENSE00000987090	71828014	71828157
ENSE00000987091	71825837	71825893
ENSE00000987094	71819714	71819900
ENSE00000987095	71819465	71819622
ENSE00000987096	71819031	71819111
ENSE00000987097	71818617	71818724
ENSE00001239711	71821876	71822007
ENSE00001239733	71828877	71829077
ENSE00001239781	71834372	71834505
ENSE00001858117	71851182	71851251
ENSE00001917960	71816298	71817476
ENSE00002498004	71831846	71831920
ENSE00003561267	71820240	71820335

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1027.7168 / max 19321.1976, expressed in 1829 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, tendon of biceps brachii, adrenal gland cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PSAP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 14 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 37 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Stomach	eqtl	4.6e-14	+0.30	10:71799095:A:G
Cells Cultured fibroblasts	sqtl	9.9e-14	-0.86	10:71803310:G:C
Pancreas	eqtl	6.4e-10	+0.31	10:71796169:T:C
Spleen	eqtl	1.0e-09	+0.21	10:71816550:C:T
Whole Blood	eqtl	1.6e-09	+0.13	10:71809561:C:T
Nerve Tibial	eqtl	1.6e-08	+0.17	10:71812126:C:T
Colon Transverse	eqtl	1.7e-08	+0.17	10:71816550:C:T
Esophagus Mucosa	sqtl	1.9e-08	-1.34	10:71803310:G:C
Esophagus Mucosa	eqtl	1.8e-06	+0.17	10:71796169:T:C
Thyroid	eqtl	2.3e-06	+0.13	10:71822995:T:A
Breast Mammary Tissue	sqtl	4.0e-06	-0.98	10:71803310:G:C
Testis	eqtl	5.9e-06	+0.09	10:71778699:T:C
Artery Aorta	eqtl	7.7e-06	-0.21	10:71851225:G:A
Skin Not Sun Exposed Suprapubic	sqtl	1.5e-05	-1.23	10:71667535:G:A
Adipose Visceral Omentum	sqtl	2.0e-05	+0.28	10:71823763:G:C
Adipose Subcutaneous	eqtl	5.3e-05	+0.15	10:71812126:C:T
Muscle Skeletal	eqtl	1.2e-04	-0.14	10:71851225:G:A
Thyroid	sqtl	1.3e-04	-1.13	10:71803310:G:C
Artery Tibial	eqtl	1.6e-04	+0.21	10:71812126:C:T
Esophagus Muscularis	eqtl	2.8e-04	+0.18	10:71811862:C:G

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
109942	964.4777	1829
109943	24.3536	1808
109944	23.5349	1789
109945	9.9650	1720
109921	2.7094	1035
109911	1.5272	654
109920	1.1489	540

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.92	gold quality
mononuclear cell	CL:0000842	99.91	gold quality
leukocyte	CL:0000738	99.90	gold quality
tendon of biceps brachii	UBERON:0008188	99.89	gold quality
right adrenal gland cortex	UBERON:0035827	99.87	gold quality
gall bladder	UBERON:0002110	99.86	gold quality
medial globus pallidus	UBERON:0002477	99.85	gold quality
right adrenal gland	UBERON:0001233	99.84	gold quality
stromal cell of endometrium	CL:0002255	99.83	gold quality
tendon	UBERON:0000043	99.83	gold quality
left adrenal gland	UBERON:0001234	99.83	gold quality
visceral pleura	UBERON:0002401	99.83	gold quality
calcaneal tendon	UBERON:0003701	99.83	gold quality
adrenal cortex	UBERON:0001235	99.81	gold quality
left adrenal gland cortex	UBERON:0035825	99.81	gold quality
prefrontal cortex	UBERON:0000451	99.80	gold quality
cranial nerve II	UBERON:0000941	99.80	gold quality
right frontal lobe	UBERON:0002810	99.80	gold quality
globus pallidus	UBERON:0001875	99.79	gold quality
cerebellar cortex	UBERON:0002129	99.79	gold quality
cerebellar hemisphere	UBERON:0002245	99.79	gold quality
adrenal gland	UBERON:0002369	99.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.79	gold quality
islet of Langerhans	UBERON:0000006	99.78	gold quality
descending thoracic aorta	UBERON:0002345	99.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.78	gold quality
granulocyte	CL:0000094	99.77	gold quality
caudate nucleus	UBERON:0001873	99.77	gold quality
postcentral gyrus	UBERON:0002581	99.77	gold quality
right atrium auricular region	UBERON:0006631	99.77	gold quality
dorsal root ganglion	UBERON:0000044	99.76	gold quality
smooth muscle tissue	UBERON:0001135	99.76	gold quality
right coronary artery	UBERON:0001625	99.76	gold quality
cardiac atrium	UBERON:0002081	99.76	gold quality
pleura	UBERON:0000977	99.75	gold quality
apex of heart	UBERON:0002098	99.75	gold quality
olfactory bulb	UBERON:0002264	99.75	gold quality
parietal pleura	UBERON:0002400	99.75	gold quality
trigeminal ganglion	UBERON:0001675	99.74	gold quality
frontal cortex	UBERON:0001870	99.74	gold quality
putamen	UBERON:0001874	99.74	gold quality
nucleus accumbens	UBERON:0001882	99.74	gold quality
cerebellum	UBERON:0002037	99.74	gold quality
renal medulla	UBERON:0000362	99.73	gold quality
ascending aorta	UBERON:0001496	99.73	gold quality
thoracic aorta	UBERON:0001515	99.73	gold quality
parietal lobe	UBERON:0001872	99.72	gold quality
heart left ventricle	UBERON:0002084	99.72	gold quality
type B pancreatic cell	CL:0000169	99.71	gold quality
endocervix	UBERON:0000458	99.71	gold quality
cardiac ventricle	UBERON:0002082	99.71	gold quality
corpus callosum	UBERON:0002336	99.71	gold quality
superior frontal gyrus	UBERON:0002661	99.71	gold quality
metanephric glomerulus	UBERON:0004736	99.71	gold quality
neocortex	UBERON:0001950	99.70	gold quality
ventricular zone	UBERON:0003053	99.70	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.70	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.70	gold quality
blood	UBERON:0000178	99.69	gold quality
heart	UBERON:0000948	99.69	gold quality
hypothalamus	UBERON:0001898	99.69	gold quality
upper lobe of left lung	UBERON:0008952	99.69	gold quality
body of uterus	UBERON:0009853	99.69	gold quality
renal glomerulus	UBERON:0000074	99.68	gold quality
aorta	UBERON:0000947	99.68	gold quality
vermiform appendix	UBERON:0001154	99.68	gold quality
left uterine tube	UBERON:0001303	99.68	gold quality
right ovary	UBERON:0002118	99.68	gold quality
synovial joint	UBERON:0002217	99.68	gold quality
upper lobe of lung	UBERON:0008948	99.68	gold quality
brain	UBERON:0000955	99.67	gold quality
coronary artery	UBERON:0001621	99.67	gold quality
pigmented layer of retina	UBERON:0001782	99.67	gold quality
forebrain	UBERON:0001890	99.67	gold quality
telencephalon	UBERON:0001893	99.67	gold quality
spleen	UBERON:0002106	99.67	gold quality
left ovary	UBERON:0002119	99.67	gold quality
adenohypophysis	UBERON:0002196	99.67	gold quality
adult mammalian kidney	UBERON:0000082	99.66	gold quality
central nervous system	UBERON:0001017	99.66	gold quality
right lobe of thyroid gland	UBERON:0001119	99.66	gold quality
tibial nerve	UBERON:0001323	99.66	gold quality
left coronary artery	UBERON:0001626	99.66	gold quality
right lung	UBERON:0002167	99.66	gold quality
CA1 field of hippocampus	UBERON:0003881	99.66	gold quality
layer of synovial tissue	UBERON:0007616	99.66	gold quality
pituitary gland	UBERON:0000007	99.65	gold quality
lymph node	UBERON:0000029	99.65	gold quality
cerebral cortex	UBERON:0000956	99.65	gold quality
left lobe of thyroid gland	UBERON:0001120	99.65	gold quality
mucosa of stomach	UBERON:0001199	99.65	gold quality
cortex of kidney	UBERON:0001225	99.65	gold quality
thyroid gland	UBERON:0002046	99.65	gold quality
lateral globus pallidus	UBERON:0002476	99.65	gold quality
cingulate cortex	UBERON:0003027	99.65	gold quality
metanephros cortex	UBERON:0010533	99.65	gold quality
adrenal tissue	UBERON:0018303	99.65	gold quality
popliteal artery	UBERON:0002250	99.64	gold quality
tibial artery	UBERON:0007610	99.64	gold quality
anterior cingulate cortex	UBERON:0009835	99.64	gold quality

Single-cell (SCXA)

Detected in 40 experiment(s), a significant marker in 33.

Experiment	Marker?	Max mean expression
E-MTAB-7381	yes	7904.40
E-GEOD-150728	yes	7852.12
E-HCAD-13	yes	7247.44
E-MTAB-9801	yes	5336.64
E-CURD-55	yes	5224.86
E-MTAB-8498	yes	4920.19
E-HCAD-15	yes	4741.45
E-MTAB-6701	yes	3736.00
E-MTAB-7407	yes	3623.61
E-MTAB-6653	yes	3308.47
E-CURD-122	yes	3205.03
E-CURD-112	yes	3081.44
E-MTAB-8410	yes	2812.33
E-MTAB-9435	yes	2779.80
E-GEOD-139324	yes	2314.38

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 160 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	1695.4
Nucleus accumbens	tissue	1392.4
Heart muscle	tissue	1333.8	high
Frontal cortex	tissue	1296.3
Locus coeruleus	tissue	1289.8
Caudate putamen	tissue	1254.0
Ovary	tissue	1210.2	medium
Hippocampus	tissue	1167.0	high
Parathyroid gland	tissue	1097.0	high
Smooth muscle	tissue	1063.8	medium
Lung	tissue	1055.1	high
Gallbladder	tissue	1047.3	high
Adrenal gland	tissue	1045.1	high
Cervix	tissue	1010.9	high
Spinal cord	tissue	1002.0
Adipose tissue	tissue	1001.3	high
Postcentral gyrus	tissue	1000.6
Spleen	tissue	985.7	high
Skeletal muscle	tissue	926.4	medium
Tongue	tissue	923.3
Lymph node	tissue	896.4	high
Medulla oblongata	tissue	890.9
Epididymis	tissue	888.7	high
Seminal vesicle	tissue	885.3	high
Urinary bladder	tissue	878.9	high
Midbrain	tissue	867.6
Liver	tissue	845.9	high
Substantia nigra	tissue	841.2
Appendix	tissue	825.2	high
Thyroid gland	tissue	823.8	high
Placenta	tissue	817.2	high
Kidney	tissue	801.6	high
Superior colliculi	tissue	800.3
Periaqueductal gray	tissue	800.1
Thalamus	tissue	799.5
Pons	tissue	795.7
Bone marrow	tissue	788.0	high
Endometrium 1	tissue	766.8	high
Prostate	tissue	725.8	high
Hypothalamus	tissue	703.0
Fallopian tube	tissue	684.7	high
Corpus callosum	tissue	684.5
Hippocampal formation	tissue	645.8
Breast	tissue	636.8	high
Stomach 1	tissue	626.4	high
Thymus	tissue	626.2
Colon	tissue	624.3	high
Retina	tissue	614.7
Rectum	tissue	586.9	high
Septum	tissue	583.9
Caudate putamen	tissue	573.2
Esophagus	tissue	570.6	medium
Cerebral cortex	tissue	556.9	high
Somatosensory cortex	tissue	556.9
Motor cortex	tissue	542.8
Putamen	tissue	541.3
Tonsil	tissue	525.4	high
Salivary gland	tissue	524.6	high
Vagina	tissue	521.2	medium
Ventral forebrain	tissue	518.9

Brain sub-regions (HPA Brain Atlas): detected in 384; highest nTPM — Lateral funiculus (white matter) (2342.1), Dorsal funiculus (white matter) (2245.6), Anterior funiculus (white matter) (1970.9), Supraoptic nucleus (1850.5), Corpus callosum, splenium (white matter) (1796.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

showing 30 of 59 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548G-5P	99.78	71.12	3085

Functional genomics

gnomAD constraint: pLI 0.952, LOEUF 0.507, missense Z 0.74 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000394936 — one region, missense o/e 0.97.

Literature-anchored findings (GeneRIF, showing 40)

• reconstruction of the order of internal duplications that gave rise to the four saposins by using phylogenetic tools (PMID:11734895)
• procathepsin D interacts with prosaposin in human breast and ovarian cancer cells. (PMID:12083803)
• crystal structure reveals a dimeric shell for lipid binding (PMID:12518053)
• data indicate that saposin C is required for acid beta-glucosidase resistance to proteolytic degradation in the cell (PMID:12813057)
• The structure of saposin C compared to other saposin-fold family members provides an explanation for function variability of this protein family. (PMID:14674747)
• model proposed in which saposin C exposes lipid antigens from intralysosomal membranes for loading onto CD1b (PMID:14716313)
• There might be a potential pleuripotent regulatory function for prosaposin in prostate cancer. (PMID:15305334)
• Prosaposin and/or saposin C via modulation of caspases expression/activity and/or PI3K/Akt signaling pathway act as a survival and anti-apoptotic factor for prostate cancer cells. (PMID:15548330)
• Saposin C stimulates prostate cancer and stromal cells growth and invasion and uPA/uPAR expression, and activates p42/44 and SAPK/JNK signaling pathways of MAPK. (PMID:15897971)
• Amplification and overexpression of PSAP was studied in prostatic neoplasms. (PMID:16080200)
• The prosaposin gene is amplified in human metastatic AI PCa cell lines and punch biopsy samples of prostate cancer xenografts and lymph node metastases. (PMID:16080200)
• determination of crystal structure of human saposins A and C to 2.0 Angstroms and 2.4 Angstroms, respectively and both reveal the compact, monomeric saposin fold (PMID:16823039)
• Saposin C or its precursor (PSAP) function as an androgen-agonist and upregulate androgen receptor and prostate-specific antigen expression/activity in androgen-responsive prostate cancer cells LNCaP, TRAMP-C1 and -C2, and CWR 22RV1. (PMID:17044040)
• Prosaposin is an androgen-target gene and its expression in androgen-responsive prostate cancer cells can be upregulated by male hormones. (PMID:17171640)
• FSAP (Factor VII-activating protease) can cleave and inactivate PDGF-BB (platelet-derived growth factor-BB) and thereby inhibits VSMC (vascular smooth-muscle cell) proliferation. (PMID:17300216)
• saposin B may facilitate lipid binding to CD1d molecules throughout the endocytic pathway (PMID:17372201)
• an unglycosylated Sap-B variant, Asn215His, which causes a fatal sphingolipid storage disease, lost the ability to extract membrane lipids at acidic pH in the presence of BMP (PMID:17561962)
• Expression of saposin C-originated saposin C may upregulate AR gene expression and activate the androgen receptor transcriptional function in an androgen-independent manner in prostate cancer cells. (PMID:17712477)
• These data for the first time demonstrate that not only saposin C or PSAP regulates AR expression/activity, but also function as an androgen-regulated gene in prostate stromal cells. (PMID:18481277)
• findings point to the role of lipid rafts in the prosaposin-triggered signalling pathway, thus supporting a role for this factor as a new component of the multimolecular signalling complex involved in the neurotrophic response. (PMID:18761669)
• Saposin B(Sap B) is not a limiting factor of the coupled Sap B-arylsulfatase A reaction in mouse kidney cells even if sulfatide has accumulated to unphysiologically high levels (PMID:19224915)
• two new patients with PSAP gene defects; one, with pSap-d, who had a severe neurovisceral dystrophy and died as a neonate, and the other with SapB-d, who presented with a metachromatic leukodystrophy-like disorder but had normal arylsulfatase activity (PMID:19267410)
• Report the up-regulation of prosaposin in the senescent fibroblasts and endothelial cells. (PMID:19471889)
• Prosaposin functions in a paracrine and endocrine fashion by stimulating the expression of thrombospondin-1 (Tsp-1) in fibroblasts present in both primary tumors and distant organs, doing so in a p53-dependent manner. (PMID:19581582)
• PSAP is involved in prostate cancer invasion. (PMID:20132547)
• The biological properties of cells from four recently described Gaucher disease patients carrying mutations in the Sap C domain of the PSAP gene have been characterized. (PMID:20484222)
• saposin C caused stimulation of androgen receptor expression and activity by associations with Src kinases (PMID:21328455)
• PSAP is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• novel esophageal squamous cell carcinoma marker PSAP was identified by mass spectrometry and immunohistochemical analysis (PMID:21743296)
• PSAP is a novel TFPI-2-interacting protein and that the binding sites are the KD2 of TFPI-2 and the C-terminus of PSAP. (PMID:21943334)
• These findings suggested that prosaposin might enhance estrogen receptor alpha-mediated signaling axis and play a role in breast cancer development and progression. (PMID:22738294)
• Urine of patients with early prostate cancer contains lower levels of light chain fragments of inter-alpha-trypsin inhibitor and prosaposin fragment or saposin B. (PMID:23417432)
• Saposin C protects glucocerebrosidase against alpha-synuclein inhibition. (PMID:24070323)
• Of the 2575 proteins identified, proteins upregulated in gallbladder cancer included several lysosomal proteins such as prosaposin, cathepsin Z and cathepsin H. (PMID:24657443)
• Mesotrypsin generated saposins A-D from prosaposin, and mature caspase-14 contributed to this process by activating mesotrypsinogen to mesotrypsin. Knockdown of these proteases markedly down-regulated saposin A synthesis in skin equivalent models. (PMID:24872419)
• findings support a lung metastasis-promoting function of the miR-23b/27b/24 cluster of miRNAs, which functions in part through the direct inhibition of PSAP in breast cancer (PMID:24966325)
• Our findings suggest a novel pharmacological approach to Sap C deficiency directed to treat major secondary pathological aspects in this disorder. (PMID:25926625)
• Data suggested that the abundance of Psap in sperm sample may be a sensitive endpoint to predict PCB exposure. (PMID:26045750)
• PSAP is a secreted biomarker. (PMID:26341737)
• Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. (PMID:26370502)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	psap	ENSDARG00000013968
mus_musculus	Psap	ENSMUSG00000004207
rattus_norvegicus	Psap	ENSRNOG00000000571

Paralogs (2): SFTPB (ENSG00000168878), PSAPL1 (ENSG00000178597)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97783) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 133 distinct phenotype terms.

Mouse phenotype (MP)	Records
ataxia	6
premature death	6
tremors	5
abnormal gait	5
hindlimb paralysis	4
demyelination	4
impaired coordination	4
limb grasping	4
abnormal lipid level	4
astrocytosis	4
Purkinje cell degeneration	3
hyperactivity	3
decreased locomotor activity	3
abnormal nervous system morphology	3
abnormal vascular endothelial cell morphology	3
axonal spheroids	3
small cerebellum	2
abnormal dorsal root ganglion morphology	2
abnormal Schwann cell morphology	2
decreased body weight	2
weight loss	2
seizures	2
abnormal lipid homeostasis	2
muscular atrophy	2
abnormal macrophage morphology	2

+108 more (showing top 25).

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
Sus scrofa	P81405	88.8%	Diamond
Bos taurus	P26779	84.4%	Diamond
Oryctolagus cuniculus	P15285	82.3%	Diamond
Gallus gallus	O13035	75.6%	Diamond
Cavia porcellus	P20097	66.7%	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
MIR7152	ncRNA	102465689
LINC03139	ncRNA	124902447
CDH23	protein-coding	64072
CHST3	protein-coding	9469
C10orf105	protein-coding	414152
VSIR	protein-coding	64115
SPOCK2	protein-coding	9806
CDH23-AS1	ncRNA	102723377
SLC29A3	protein-coding	55315

Protein

Protein identifiers

Prosaposin — P07602 (reviewed: P07602)

Alternative names: Proactivator polypeptide

All UniProt accessions (2): A0A0J9YXB8, P07602

UniProt curated annotations — full annotation on UniProt →

Function. Saposins are specific low-molecular mass non-enzymatic glycoproteins that act as activator proteins for lysosomal sphingolipid-degrading enzymes, facilitating the hydrolysis of sphingolipids by extracting lipid substrates from membranes and presenting them to their respective enzymes. They are derived from a common precursor protein, prosaposin, which is proteolytically cleaved to yield four homologous proteins (saposin A, B, C, and D), each with distinct but partially overlapping lipid and enzyme specificities. Behaves as a myelinotrophic and neurotrophic factor, these effects are mediated by its G protein-coupled receptors, GPR37 and GPR37L1, undergoing ligand-mediated internalization followed by ERK phosphorylation signaling. acts as an essential lysosomal cofactor that activates galactocerebrosidase (GALC, EC 3.2.1.46) by facilitating enzyme access to its membrane-embedded galactosylceramide substrate, the principal lipid component of myelin. Stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A ARSA (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Forms a solubilizing complex with the substrates of the sphingolipid hydrolases. Acts as an essential lysosomal cofactor that activates acid beta-glucosylceramidases (EC 3.2.1.45) by altering lipid bilayer properties to facilitate enzyme access to its membrane-embedded glucosylceramide substrate, while also protecting glucocerebrosidase from intralysosomal proteolytic degradation. Acts as a lysosomal activator protein that stimulates acid ceramidase (EC 3.5.1.23) by solubilizing and presenting ceramide substrates at the lipid-water interface, facilitating their hydrolysis into sphingosine and fatty acids. It also activates acid sphingomyelinase (EC 3.1.4.12), though ceramide catabolism represents its primary physiological role.

Subunit / interactions. Prosaposin exists as a roughly half-half mixture of monomers and disulfide-linked dimers. Monomeric prosaposin interacts (via C-terminus) with sortilin/SORT1, the interaction is required for targeting to lysosomes. Interacts with GRN; facilitates lysosomal delivery of progranulin from the extracellular space and the biosynthetic pathway. Homodimer.

Subcellular location. Lysosome Secreted.

Post-translational modifications. The lysosomal precursor is proteolytically processed to 4 small peptides, which are similar to each other and are sphingolipid hydrolase activator proteins. N-linked glycans show a high degree of microheterogeneity. The one residue extended Saposin-B-Val is only found in 5% of the chains.

Disease relevance. Combined saposin deficiency (PSAPD) [MIM:611721] An autosomal recessive storage disorder characterized by hepatosplenomegaly and severe neurologic disease, due to absence of all saposins. PSAPD has a fatal outcome in infancy. The disease is caused by variants affecting the gene represented in this entry. Metachromatic leukodystrophy due to saposin B deficiency (MLDSAPB) [MIM:249900] A form of metachromatic leukodystrophy biochemically characterized by tissue accumulation of cerebroside-3-sulfate, saposin B deficiency, and normal arylsulfatase A activity. Clinical manifestations include periventricular white matter abnormalities, demyelination, and peripheral neuropathy. Additional neurological features include dysarthria, ataxic gait, psychomotor regression, seizures, cognitive decline and spastic quadriparesis. The disease is caused by variants affecting the gene represented in this entry. Gaucher disease, atypical, due to saposin C deficiency (GDSAPC) [MIM:610539] A disease characterized by marked glucosylceramide accumulation in the spleen without having a deficiency of glucosylceramide-beta glucosidase characteristic of classic Gaucher disease. Gaucher disease is a lysosomal storage disorder characterized by skeletal deterioration, hepatosplenomegaly, and organ dysfunction. There are several subtypes based on the presence and severity of neurological involvement. The disease is caused by variants affecting the gene represented in this entry. Krabbe disease, atypical, due to saposin A deficiency (KRBSAPA) [MIM:611722] An autosomal recessive disorder of galactosylceramide metabolism. Clinical features include neurologic regression around age 3 months, loss of spontaneous movements, hyporeflexia, generalized brain atrophy, and diffuse white matter dysmyelination. The disease is caused by variants affecting the gene represented in this entry. Defects in PSAP saposin-D region are found in a variant of Tay-Sachs disease (GM2-gangliosidosis). Parkinson disease 24, autosomal dominant (PARK24) [MIM:619491] An autosomal dominant form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. PARK24 shows incomplete penetrance. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. Saposin-B co-purifies with 1 molecule of phosphatidylethanolamine.

Isoforms (3)

UniProt ID	Names	Canonical?
P07602-1	Sap-mu-0	yes
P07602-2	Sap-mu-6
P07602-3	Sap-mu-9

RefSeq proteins (3): NP_001035930, NP_001035931, NP_002769* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003119	SAP_A	Domain
IPR007856	SapB_1	Domain
IPR008138	SapB_2	Domain
IPR008139	SaposinB_dom	Domain
IPR008373	Saposin	Family
IPR011001	Saposin-like	Homologous_superfamily
IPR021165	Saposin_chordata	Family
IPR051428	SFTPB-like	Family

Pfam: PF02199, PF03489, PF05184

UniProt features (73 total): helix 20, disulfide bond 12, sequence variant 9, chain 6, domain 6, propeptide 5, glycosylation site 5, mutagenesis site 3, splice variant 2, signal peptide 1, site 1, sequence conflict 1, strand 1, turn 1

Structure

Experimental structures (PDB)

21 structures by resolution:

PDB	Title	Method	Resolution (Å)
3BQP	Crystal Structure of Human Saposin D (orthorhombic)	X-RAY DIFFRACTION	1.3
9I63	Synthetic Human Saposin D glycoprotein	X-RAY DIFFRACTION	1.65
4UEX	Structure of human Saposin A at lysosomal pH	X-RAY DIFFRACTION	1.8
4DDJ	Crystal structure of saposin A in complex with lauryldimethylamine-N-oxide (LDAO)	X-RAY DIFFRACTION	1.9
2DOB	Crystal Structure of Human Saposin A	X-RAY DIFFRACTION	2
3BQQ	Crystal Structure of Human Saposin D (triclinic)	X-RAY DIFFRACTION	2
2RB3	Crystal Structure of Human Saposin D	X-RAY DIFFRACTION	2.1
4V2O	Structure of saposin B in complex with chloroquine	X-RAY DIFFRACTION	2.13
1N69	Crystal structure of human saposin B	X-RAY DIFFRACTION	2.2
6SLR	Structure of saposin B in complex with atovaquone	X-RAY DIFFRACTION	2.38
2GTG	Crystal Structure of Human Saposin C	X-RAY DIFFRACTION	2.4
2QYP	Orthorhombic Crystal Structure of Human Saposin C Dimer in Open Conformation	X-RAY DIFFRACTION	2.45
2R0R	Crystal Structure of Human Saposin D variant SapD K9E	X-RAY DIFFRACTION	2.5
2R1Q	Crystal Structure of Iodinated Human Saposin D in Space Group C2221	X-RAY DIFFRACTION	2.5
2Z9A	Crystal Structure of Human Saposin C Dimer in Open Conformation	X-RAY DIFFRACTION	2.5
9AXG	Human saposin B in the presence of globotriaosylceramide-NBD	X-RAY DIFFRACTION	2.68
8EQU	Structure of SARS-CoV-2 Orf3a in late endosome/lysosome-like environment, Saposin A …	ELECTRON MICROSCOPY	2.8
9EKO	A chimeric hybrid protein fused with the FGFR3 Transmembrane Domain	X-RAY DIFFRACTION	2.9
9AVS	Human alpha-galactosidase A in complex with saposin B	X-RAY DIFFRACTION	3.53
1M12	NMR solution structure of human Saposin C	SOLUTION NMR
1SN6	NMR solution structure of human Saposin C in SDS micelles	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07602-F1	73.90	0.17

Human Protein Atlas

Protein class: Transporters, Electrochemical Potential-driven transporters, Predicted membrane proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

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

Catalytic / active sites (1)

Position	Role
215	not glycosylated; in variant mldsapb ile-217

Disulfide bonds (12)

Type	Positions
Disulfide bond	63–138, 66–132, 94–106, 198–271, 201–265, 230–241, 315–388, 318–382, 346–357, 409–482, 412–476, 440–451

Glycosylation sites (5)

Type	Positions
N-linked (glcnac…) asparagine	80, 101, 332, 426
N-linked (glcnac…) (complex) asparagine	215

Mutagenesis-validated functional residues (3)

Position	Phenotype
106	unable to mobilize lipids out of the membrane.
132	unable to mobilize lipids out of the membrane.
240	strongly decreases stimulation of cerebroside sulfate hydrolysis.

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 19; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

19 pathways:

ID	Pathway	Evidence
R-HSA-418594	G alpha (i) signalling events	curated
R-HSA-9840310	Glycosphingolipid catabolism	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-375276	Peptide ligand-binding receptors	curated
R-HSA-114608	Platelet degranulation	curated
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-500792	GPCR ligand binding	—
R-HSA-1660662	Glycosphingolipid metabolism	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-76005	Response to elevated platelet cytosolic Ca2+	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—
R-HSA-428157	Sphingolipid metabolism	—

MSigDB gene sets: 685 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_LYSOSOMAL_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_GROWTH, HSIAO_HOUSEKEEPING_GENES, GOBP_VACUOLAR_TRANSPORT, KEGG_LYSOSOME, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, MARTINEZ_RB1_TARGETS_UP

GO Biological Process (10): sphingolipid metabolic process (GO:0006665), lysosomal transport (GO:0007041), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), gene expression (GO:0010467), regulation of autophagy (GO:0010506), regulation of lipid metabolic process (GO:0019216), prostate gland growth (GO:0060736), epithelial cell differentiation involved in prostate gland development (GO:0060742), ganglioside GM1 transport to membrane (GO:1905572), lipid metabolic process (GO:0006629)

GO Molecular Function (13): protease binding (GO:0002020), phospholipid binding (GO:0005543), enzyme activator activity (GO:0008047), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), scaffold protein binding (GO:0097110), ganglioside GM1 binding (GO:1905573), ganglioside GM2 binding (GO:1905574), ganglioside GM3 binding (GO:1905575), ganglioside GT1b binding (GO:1905576), ganglioside GP1c binding (GO:1905577), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (8): extracellular region (GO:0005576), lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), plasma membrane (GO:0005886), azurophil granule membrane (GO:0035577), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062)

Reactome top-level categories

14 top-level categories:

Category	Pathways
Signaling by GPCR	2
Response to elevated platelet cytosolic Ca2+	1
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
Innate Immune System	1
Glycosphingolipid metabolism	1
Sphingolipid metabolism	1
Immune System	1
Signal Transduction	1
GPCR ligand binding	1
Metabolism of lipids	1
Metabolism	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

41 GO namespaces:

Category	Terms
ganglioside binding	5
carboxylic acid binding	4
lipid metabolic process	2
developmental process involved in reproduction	2
prostate gland development	2
protein binding	2
binding	2
lysosome	2
vacuolar transport	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
macromolecule biosynthetic process	1
autophagy	1
regulation of catabolic process	1
regulation of primary metabolic process	1
organ growth	1
epithelial cell differentiation	1
ceramide transport	1
glycolipid transport	1
carboxylic acid transport	1
localization within membrane	1
primary metabolic process	1
enzyme binding	1
lipid binding	1
catalytic activity	1
enzyme regulator activity	1
molecular function activator activity	1
identical protein binding	1
protein dimerization activity	1
monocarboxylic acid binding	1
cellular anatomical structure	1
lytic vacuole	1
lytic vacuole membrane	1
endosome	1
membrane	1
cell periphery	1
lysosomal membrane	1
secretory granule membrane	1
azurophil granule	1
vacuolar lumen	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 17 of 32 annotations. The rest are phylogenetic / computational / electronic (IEA).

17 experimentally-supported GO terms:

GO term	NS	Evidence
ganglioside GM1 transport to membrane	BP	direct assay
gene expression	BP	direct assay
lysosomal transport	BP	direct assay
extracellular exosome	CC	high-throughput assay
extracellular region	CC	high-throughput assay
late endosome	CC	direct assay
lysosome	CC	direct assay
ganglioside GM1 binding	MF	direct assay
ganglioside GM2 binding	MF	direct assay
ganglioside GM3 binding	MF	direct assay
ganglioside GP1c binding	MF	direct assay
ganglioside GT1b binding	MF	direct assay
identical protein binding	MF	physical interaction
phospholipid binding	MF	direct assay
protease binding	MF	physical interaction
protein homodimerization activity	MF	direct assay
scaffold protein binding	MF	physical interaction

Protein interactions and networks

IntAct

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

22 partners by confidence:

Partner	Interaction type	MIscore	Records
GRN	physical association	0.700	4
ZBED1	physical association	0.670	4
APP	physical association	0.560	3
APPBP2	physical association	0.560	3
CSNK1D	physical association	0.560	3
LYN	physical association	0.560	3
PEX5	physical association	0.560	3
CASP14	physical association	0.470	3
ERBB2	physical association	0.370	1
SMAD2	physical association	0.370	1
SMAD9	physical association	0.370	1
UBE3A	physical association	0.370	1
NAT14	association	0.350	1
PRSS3	proximity	0.270	1
CELSR1	physical association	0.000	1
COPS6	physical association	0.000	1
DISC1	physical association	0.000	1
DYRK1A	physical association	0.000	1
HSPA13	physical association	0.000	1
MAFF	physical association	0.000	1
PRAG1	physical association	0.000	1
SGCG	physical association	0.000	1

BioGRID (154 interactions; top human partners by supporting records): USP48 (Affinity Capture-MS; 3 records), CTSB (Affinity Capture-MS; 2 records), FBXO6 (Affinity Capture-MS; 2 records), ZBED1 (Two-hybrid; 2 records), ZRANB1 (Affinity Capture-MS; 2 records), ACTB (Co-fractionation), AK2 (Co-fractionation), AK4 (Co-fractionation), APPBP2 (Two-hybrid), BAG3 (Co-fractionation), BAP1 (Affinity Capture-MS), BCAT1 (Co-fractionation), BCL6 (Affinity Capture-MS), BRCA1 (Two-hybrid), C1QBP (Co-fractionation)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
TFEB	“up-regulates quantity by expression”	PSAP	“transcriptional regulation”

Protein complexes (CORUM) (1)

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

1 complexes by size:

Complex	Subunits	Members
ASAH1-NR5A1-SAPD complex	3	ASAH1, NR5A1, PSAP

Disease & clinical

Genetic variants

Variant evidence for PSAP: 1,021 ClinVar records (91 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

1,021 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	48
Uncertain significance	302
Likely benign	479
Benign	47

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 91 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
13365	NM_002778.4(PSAP):c.1A>T (p.Met1Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
860182	NM_002778.4(PSAP):c.1A>G (p.Met1Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
13366	NM_002778.4(PSAP):c.577-1G>T	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1455040	NM_002778.4(PSAP):c.889G>T (p.Glu297Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2735420	NM_002778.4(PSAP):c.148C>T (p.Gln50Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1471743	NM_002778.4(PSAP):c.375+1G>T	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
968905	NM_002778.4(PSAP):c.721-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1324967	NM_002778.4(PSAP):c.720+2_720+5del	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1523203	NM_002778.4(PSAP):c.576+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
13374	NM_002778.4(PSAP):c.577-2A>G	Pathogenic	criteria provided, single submitter	2
977281	NM_002778.4(PSAP):c.816_823del (p.Asp272fs)	Pathogenic	criteria provided, single submitter	2
562227	NM_002778.4(PSAP):c.1268del (p.Leu423fs)	Pathogenic	criteria provided, single submitter	1
915358	NM_002778.4(PSAP):c.778-1889C>T	Pathogenic	criteria provided, single submitter	1
942712	NM_002778.4(PSAP):c.1348C>T (p.Gln450Ter)	Pathogenic	criteria provided, single submitter	1
1070932	NM_002778.4(PSAP):c.1120del (p.Glu374fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PSAP’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.

AlphaMissense

666 missense substitutions predicted likely pathogenic (of 3,471 scored), across 220 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
C518	7	0.990	0.996
C48	7	0.988	0.994
C503	7	0.988	0.997
C512	7	0.986	0.996
C265	7	0.984	0.993
C440	7	0.984	0.993
C476	7	0.984	0.993
C412	7	0.983	0.994
C94	7	0.982	0.994
C132	7	0.981	0.991
C33	7	0.979	0.994
C451	7	0.979	0.991
C138	7	0.978	0.990
C66	7	0.974	0.989
C382	7	0.974	0.988
C42	7	0.973	0.986
C106	7	0.971	0.984
C201	7	0.971	0.988
C230	7	0.969	0.988
C409	7	0.967	0.982

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

7 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.32e-07
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	6.58e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	2.76e-05
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000238
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000891
Lung Squamous Cell Carcinoma (validation)	unfavorable	0.000902

Disease associations

OMIM: gene MIM:176801 | disease phenotypes: MIM:249900, MIM:619491, MIM:611721, MIM:611722, MIM:610539

GenCC curated gene-disease

6 curated gene-disease records:

Disease	Classification	Inheritance	Records
Krabbe disease due to saposin A deficiency	Definitive	Autosomal recessive	4
PSAP-related sphingolipidosis	Definitive	Autosomal recessive
metachromatic leukodystrophy due to saposin B deficiency	Strong	Autosomal recessive	4
Gaucher disease due to saposin C deficiency	Strong	Autosomal recessive	4
combined PSAP deficiency	Strong	Autosomal recessive	4
Parkinson disease 24, autosomal dominant, susceptibility to	Strong	Autosomal dominant	2

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

4 validity classifications:

Disease	Classification	Inheritance
metachromatic leukodystrophy due to saposin B deficiency	Definitive	AR
Krabbe disease due to saposin A deficiency	Moderate	AR
Gaucher disease due to saposin C deficiency	Definitive	AR
combined PSAP deficiency	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (18 panels, 18 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

18 panels:

Panel	Rating
Adult-onset neurological disorders	green
DDG2P	green
Early onset or syndromic epilepsy	green
Fetal anomalies	green
Hypotonic infant	green
Inherited white matter disorders	green
Intellectual disability	green
Krabbe disease - Saposin A deficiency	green
Leukodystrophy, adult onset	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Lysosomal storage disorder	green
Mucopolysaccharideosis, Gaucher, Fabry	green
Neurodegenerative disorders, adult onset	green
Paediatric disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green
White matter disorders and cerebral calcification - childhood onset	green

Mondo (7): metachromatic leukodystrophy due to saposin B deficiency (MONDO:0009590), Parkinson disease 24, autosomal dominant, susceptibility to (MONDO:0859183), combined PSAP deficiency (MONDO:0012719), metachromatic leukodystrophy (MONDO:0018868), Krabbe disease due to saposin A deficiency (MONDO:0012720), Gaucher disease due to saposin C deficiency (MONDO:0012517), PSAP-related sphingolipidosis (MONDO:0100517)

Orphanet (5): Metachromatic leukodystrophy (Orphanet:512), Encephalopathy due to prosaposin deficiency (Orphanet:139406), Krabbe disease (Orphanet:487), Atypical Gaucher disease due to saposin C deficiency (Orphanet:309252), Gaucher disease (Orphanet:355)

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D007966	Leukodystrophy, Metachromatic	C10.228.140.163.100.362.550; C10.228.140.163.100.435.825.850.500; C10.228.140.695.625.550; C10.314.400.550; C16.320.565.189.362.550; C16.320.565.189.435.825.850.500; C16.320.565.398.641.803.925.500; C16.320.565.595.554.825.850.500; C18.452.132.100.362.550; C18.452.132.100.435.825.850.500; C18.452.584.563.641.803.925.500; C18.452.648.189.362.550; C18.452.648.189.435.825.850.500; C18.452.648.398.641.803.925.500; C18.452.648.595.554.825.850.500
C567125	Combined Saposin Deficiency *(supp.)*
C566435	Gaucher Disease, Atypical, Due To Saposin C Deficiency *(supp.)*
C567097	Krabbe Disease, Atypical, due to Saposin A Deficiency *(supp.)*
C562609	Metachromatic Leukodystrophy due to Saposin B Deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3580523 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 24,197 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL7301	FENRETINIDE	3	24,197

PharmGKB: 1 entry (CPIC guideline: no)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.16	Kd	6900	nM	FENRETINIDE

PubChem BioAssay actives

2 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2E,4E,6E,8E)-N-(4-hydroxyphenyl)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenamide	1695703: Binding affinity to human saposin D (1 to 81 residues) expressed in Escherichia coli at 25 degree C by electronic absorption spectroscopy	kd	6.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, increases abundance, affects expression, decreases expression	4
Valproic Acid	affects expression, increases expression	4
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Acetaminophen	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	increases expression	2
ginger extract	affects cotreatment, affects expression, increases abundance	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
sodium arsenate	decreases expression	1
titanium dioxide	affects binding, increases expression	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
octa-2,4,6-trienoic acid	increases expression	1
yessotoxin	increases expression	1
chloropicrin	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
LG 100815	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 8 binding, 4 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3585104	ADMET	Binding affinity to human saposin B expressed in Escherichia coli BL21 Gold (DE3) at 120 uM using 15 uM sapB and 50 mM MES and 4% THF at pH 5.5 and 25 degC by ITC method	The antimalarial drug atovaquone binds to saposin B with comparable affinity to coenzyme Q10 — *Medchemcomm*
CHEMBL4700523	Binding	Binding affinity to human saposin D (1 to 81 residues) expressed in Escherichia coli assessed as decrease in BODIPY-TR labeled ceramide solubilization in sodium phosphate buffer measured after 30 mins by fluorescence assay	Fenretinide binding to the lysosomal protein saposin D alters ceramide solubilization and hydrolysis — *RSC Med Chem*

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 1 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B2CB	Abcam HeLa PSAP KO	Cancer cell line	Female
CVCL_D5F6	HeLa::TMEM192-3xHA PSAP KO	Cancer cell line	Female
CVCL_D9PW	Ubigene HEK293 PSAP KO	Transformed cell line	Female
CVCL_E2I1	HAP1 PSAP (-) 1	Cancer cell line	Male
CVCL_E2I2	HAP1 PSAP (-) 2	Cancer cell line	Male
CVCL_F0Q2	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) PSAP-/-	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

showing 60 of 243 trials:

NCT	Phase	Status	Title
NCT00331656	Phase 4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	Phase 4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT04283227	Phase 3	ACTIVE_NOT_RECRUITING	OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)
NCT00839033	Phase 3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	Phase 3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	Phase 3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	Phase 3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	Phase 3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	Phase 3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	Phase 3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	Phase 3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	Phase 3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	Phase 3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	Phase 3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	Phase 3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	Phase 3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT00383448	Phase 2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT01043640	Phase 2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01303146	Phase 2	COMPLETED	Efficacy METAZYM for the Treatment Metachromatic Leukodystrophy Treated With Hematopoietic Stem Cell Transplantation
NCT02171104	Phase 2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT03392987	Phase 2	COMPLETED	A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)
NCT03771898	Phase 2	COMPLETED	A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy
NCT00668564	Phase 2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
NCT07740512	Phase 2	NOT_YET_RECRUITING	Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of PLX-200 in Pediatric Patients (Master Protocol)
NCT01074359	Phase 2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	Phase 2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	Phase 2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	Phase 2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	Phase 2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	Phase 2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	Phase 2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	Phase 2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	Phase 2	RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	Phase 2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00418561	Phase 1	COMPLETED	Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)
NCT01586455	Phase 1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT00252252	Phase 1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	Phase 1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	Phase 1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	Phase 1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	Phase 1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis
NCT05730842	Phase 1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT00176904	Phase 2/3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT01372228	Phase 1/2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT01510028	Phase 1/2	COMPLETED	Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)
NCT01560182	Phase 1/2	COMPLETED	Gene Therapy for Metachromatic Leukodystrophy (MLD)
NCT01801709	Phase 1/2	COMPLETED	Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy
NCT01887938	Phase 1/2	COMPLETED	An Efficacy and Safety Study of HGT-1110 in Participants With Metachromatic Leukodystrophy
NCT02559830	Phase 1/2	UNKNOWN	Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy
NCT00004378	Not specified	COMPLETED	Stem Cell Transplantation (SCT) for Genetic Diseases
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT00639132	Not specified	WITHDRAWN	The Natural History of Metachromatic Leukodystrophy
NCT00683189	Not specified	COMPLETED	Effect of Warfarin in the Treatment of Metachromatic Leukodystrophy
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01963650	Not specified	TERMINATED	Natural History Study of Children With Metachromatic Leukodystrophy
NCT02021266	Not specified	NO_LONGER_AVAILABLE	Single Patient Expanded Access Protocol: Metabolic Boost
NCT02084121	Not specified	NO_LONGER_AVAILABLE	Allogeneic Stem Cell Transplantation for the Treatment of Multiple Sclerosis (Compassionate Use)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PSAP across ~30M SureChEMBL compounds — explore on Sugi Predict.