ACP5

Summary

ACP5 (acid phosphatase 5, tartrate resistant, HGNC:124) is a protein-coding gene on chromosome 19p13.2, encoding Tartrate-resistant acid phosphatase type 5 (P13686). Involved in osteopontin/bone sialoprotein dephosphorylation.

This gene encodes an iron containing glycoprotein which catalyzes the conversion of orthophosphoric monoester to alcohol and orthophosphate. It is the most basic of the acid phosphatases and is the only form not inhibited by L(+)-tartrate.

Source: NCBI Gene 54 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Spondyloenchondrodysplasia with immune dysregulation (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 359 total — 38 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 92
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001611

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:124
Approved symbol	ACP5
Name	acid phosphatase 5, tartrate resistant
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	TRAP, HPAP, TRAcP
Ensembl gene	ENSG00000102575
Ensembl biotype	protein_coding
OMIM	171640
Entrez	54

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 26 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay

ENST00000218758, ENST00000412435, ENST00000588079, ENST00000588524, ENST00000588625, ENST00000589792, ENST00000590832, ENST00000591319, ENST00000592659, ENST00000592828, ENST00000648477, ENST00000649386, ENST00000695791, ENST00000695809, ENST00000695810, ENST00000695811, ENST00000695812, ENST00000695813, ENST00000695814, ENST00000695815, ENST00000695816, ENST00000695817, ENST00000695818, ENST00000695819, ENST00000695820, ENST00000695821, ENST00000695838, ENST00000889665, ENST00000889666, ENST00000889667, ENST00000889668, ENST00000944462, ENST00000944463, ENST00000944464

RefSeq mRNA: 5 — MANE Select: NM_001611 NM_001111034, NM_001111035, NM_001111036, NM_001322023, NM_001611

CCDS: CCDS12265

Canonical transcript exons

ENST00000648477 — 5 exons

Exon	Start	End
ENSE00003834800	11577593	11577645
ENSE00003890767	11577057	11577317
ENSE00003965042	11576243	11576588
ENSE00003965043	11576716	11576843
ENSE00003965045	11574660	11575252

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 99.79.

FANTOM5 (CAGE): breadth broad, TPM avg 61.6037 / max 3245.6171, expressed in 726 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179267	34.5418	309
179275	11.6813	526
179268	11.0891	374
179273	2.2148	192
179276	0.5695	237
179274	0.5393	153
179271	0.4250	150
179272	0.2979	151
179270	0.1265	53
179266	0.0605	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	99.79	gold quality
upper lobe of left lung	UBERON:0008952	96.61	gold quality
right lung	UBERON:0002167	96.57	gold quality
upper lobe of lung	UBERON:0008948	96.56	gold quality
lower lobe of lung	UBERON:0008949	95.83	gold quality
tibia	UBERON:0000979	95.80	gold quality
granulocyte	CL:0000094	94.98	gold quality
lymph node	UBERON:0000029	93.54	gold quality
spleen	UBERON:0002106	93.39	gold quality
lung	UBERON:0002048	92.93	gold quality
rectum	UBERON:0001052	92.66	gold quality
vermiform appendix	UBERON:0001154	91.90	gold quality
gall bladder	UBERON:0002110	91.82	gold quality
adult organism	UBERON:0007023	91.50	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.90	gold quality
body of stomach	UBERON:0001161	90.83	gold quality
monocyte	CL:0000576	90.66	gold quality
leukocyte	CL:0000738	90.55	gold quality
mononuclear cell	CL:0000842	90.37	gold quality
colonic epithelium	UBERON:0000397	90.10	gold quality
skin of abdomen	UBERON:0001416	89.99	gold quality
esophagus mucosa	UBERON:0002469	89.60	gold quality
adult mammalian kidney	UBERON:0000082	89.38	gold quality
lower esophagus mucosa	UBERON:0035834	89.32	gold quality
skin of leg	UBERON:0001511	89.29	gold quality
ectocervix	UBERON:0012249	89.24	gold quality
small intestine	UBERON:0002108	88.94	gold quality
endocervix	UBERON:0000458	88.67	gold quality
stromal cell of endometrium	CL:0002255	88.53	gold quality
caecum	UBERON:0001153	88.36	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	12301.12
E-MTAB-8322	yes	7915.78
E-CURD-112	yes	4051.61
E-MTAB-8207	yes	2310.65
E-HCAD-15	yes	2142.32
E-MTAB-7407	yes	1863.23
E-CURD-126	yes	1451.97
E-ANND-5	yes	714.92
E-HCAD-1	yes	85.65
E-CURD-122	yes	77.15
E-MTAB-10553	yes	48.52
E-HCAD-9	yes	19.35
E-ANND-3	yes	9.75
E-GEOD-110499	no	55.44
E-CURD-120	no	31.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FLCN, FOS, FOXM1, IRF4, JDP2, MITF, MYC, NFATC1, NFATC2, NFKB, NR2C2, SP1, SPI1, TFE3, TFEC, YY1

miRNA regulators (miRDB)

17 targeting ACP5, 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-3912-5P	99.95	66.11	925
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-1470	98.11	63.53	399
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-1227-3P	97.36	66.94	834
HSA-MIR-6749-5P	89.28	58.87	75

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Serum tartrate-resistant acid phosphatase isoforms in rheumatoid arthritis. (PMID:11983200)
• One isoenzyme, but not the other (5b but not 5a) correlates with other markers of bone turnover and bone mineral density. (PMID:12073156)
• serum tartrate resistant tartrate resistant acid phosphatase 5 is useful as a marker for bone resorption (PMID:12589973)
• specific and sensitive marker of bone resorption and for the early detection of the spreading of breast cancer cells to bone (PMID:12820342)
• Increased tartrate-resistant acid phosphatase isoform 5b is associated with multiple myeloma bone disease (PMID:12845688)
• In human serum, TRACP 5b circulates in a large complex that contained alpha2M and calcium. (PMID:12901871)
• The Human serum tartrate-resistant acid phosphatase exists as two enzyme isoforms (TRACP 5a and 5b), derived by differential, post-translational processing of a common gene product. (PMID:15542543)
• Elevated tartrate-resistant acid phosphatase 5b in serum is associted with extensive bone metastasis in breast cancer (PMID:15701839)
• Results lead to hypothesize that the capacity of osteoblast-like cells to endocytose TRACP (ACP5) is important for the removal of this enzyme during or following the bone resorptive activity of the osteoclast. (PMID:15878315)
• a role of the loop residue D158 in catalysis in the cleaved enzyme. (PMID:15950921)
• crystal structures at 2.2A resolution demonstrate that the repression loop exhibits significant conformational flexibility, and the observed alternate binding mode suggests a possible inhibitory role for this loop (purple Acid phosphatase) (PMID:15993892)
• The results suggest that in endothelial cells of the afferent arterioles, mesangial cells, and lymphocytes the cellular activities are regulated by high constitutive phosphotyrosine phosphatase. (PMID:16200454)
• the MCP-1-induced TRAP(+)/CTR(+) multinuclear cells represent an arrested stage in osteoclast differentiation, after NFATc1 induction and cellular fusion but prior to the development of bone resorption activity (PMID:16280328)
• These results suggest that the protease-sensitive loop peptide, redox-active iron, and disulfide bond are important regulatory sites in TRACP. (PMID:16620768)
• TRAP might be useful as a marker of progression of malignant disease and could be a potential target for cancer therapies. (PMID:16869970)
• This work suggests that tumour derived TRAP contributes to the raised enzyme activity found in the serum of breast cancer patients. (PMID:17088078)
• TRAP 5b may serve as a new additional marker of bone resorption in the assessment of renal osteodystrophy. (PMID:17357281)
• heterozygous mutation (R714C) of the osteopetrosis gene, pleckstrin homolog domain containing family M (with run domain) member 1 (PLEKHM1), impairs vesicular acidification and increases TRACP secretion in osteoclasts (PMID:17997709)
• Myeloma-osteoclast interactions stimulated the production of TRAP, cathepsin K, MMP-1, -9, and uPA (PMID:18053985)
• Serum TRACP5b may be a good marker for serum bone resorption in predialysis chronic kidney disease patients, as it is not affected by renal dysfunction. (PMID:18221403)
• Over-expression of monomeric tartrate resistant acid phosphatase, but not the dimeric form in adipose tissue leads to early onset spontaneous hyperplastic obesity (PMID:18320034)
• This study was undertaken to examine the significance of serum TRACP isoforms 5a and 5b as disease markers of inflammation and bone destruction in rheumatoid arthritis. (PMID:18410226)
• Tartrate-resistant acid phosphatase (TRAP) 5b is a new marker of bone resorption that is unaffected by renal dysfunction (PMID:18421493)
• These results indicate that the differences between TRAP 5a and 5b consist not only of a difference in modification by sialic acid but differences in other sugar chain structures. (PMID:18703035)
• Data show that tartrate-resistant acid phosphatase activity is modulated during osteoblastic differentiation, possibly in response to the redox state of the cell, since it seemed to depend on suitable levels of reduced glutathione. (PMID:18979172)
• Data showed that serum TRACP5b was a sensitive and useful parameter for the evaluation of age-related changes of bone absorption. (PMID:19026169)
• Tartrate-resistant acid phosphatase 5a remained unaffected by exercise training, consistent with our hypothesis that it is associated with increased adipose tissue in obese individuals (PMID:19765782)
• TRACP 5b activity and its interval change after treatment bore a prognostic role in breast cancer patients with bone metastasis and a high baseline serum TRACP 5b activity. (PMID:20416078)
• Serum TRACP5b activity test is a potentially useful adjunct in diagnosing and monitoring bone metastasis in non-small cell lung cancer (PMID:20932965)
• The presence of TRAP-positive macrophages in bone metastases could, together with cancer cells and osteoclasts, contribute to the elevated levels of serum TRAP activity observed in patients with bone metastases. (PMID:20967488)
• osteopontin is regulated by TRAP in the pathogenesis of common autoimmune disorders (PMID:21217752)
• Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature (PMID:21217755)
• Serum TRACP5a is a macrophage-derived inflammation marker associated with CVD risk (PMID:21300043)
• TRAP is a novel human adipokine produced by macrophages and secreted from the subcutaneous adipose tissue in vivo and in vitro. TRAP is involved in fat accumulation and adipose inflammation. (PMID:21386798)
• TRAcP 5b could be useful as a diagnostic tool for the detection of bone metastases in patients with breast cancer. (PMID:22335021)
• Data from studies in relatively young, postmenopausal women suggest that serum level of TRAP 5b (a marker of bone resorption) can be lowered by dietary factors (i.e., low-fat vitamin D- and calcium-fortified cheese). (PMID:22357739)
• The ACP5 gene is neither associated with the occurrence nor the curve severity of adolescent idiopathic scoliosis. (PMID:22490295)
• The results showed that both OC and TRACP-5b values were at their highest during the ovulation period, and the activity of TRACP-5b was more significant than that of OC. Furthermore, the changes in sex hormone secretion involved in OC and TRACP-5b showed specific patterns during the menstrual cycle. (PMID:22517558)
• Tartrate-resistant acid phosphatase stain-ing of bone marrow osteoclasts cannot serve as a tool to determine the time of death of a patient. (PMID:22844067)
• Immunohistochemistry revealed that ACP5 expression was positively correlated with FoxM1 expression in human HCC tissues, and their coexpression was associated with poor prognoses (PMID:23604121)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	acp5a	ENSDARG00000019763
mus_musculus	Acp5	ENSMUSG00000001348
rattus_norvegicus	Acp5	ENSRNOG00000046261
caenorhabditis_elegans	F02E9.7	WBGENE00008531

Protein

Protein identifiers

Tartrate-resistant acid phosphatase type 5 — P13686 (reviewed: P13686)

Alternative names: Tartrate-resistant acid ATPase, Type 5 acid phosphatase

All UniProt accessions (10): P13686, A0A3B3IS75, A0A8Q3SI79, A0A8Q3WKS0, A0A8Q3WKS1, A0A8Q3WKT0, A0A8Q3WLB6, K7EIP0, K7EJD9, K7ESF2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in osteopontin/bone sialoprotein dephosphorylation. Its expression seems to increase in certain pathological states such as Gaucher and Hodgkin diseases, the hairy cell, the B-cell, and the T-cell leukemias.

Subunit / interactions. Exists either as monomer or, after proteolytic processing, as a dimer of two chains linked by disulfide bond(s).

Subcellular location. Lysosome.

Disease relevance. Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) [MIM:607944] A disease characterized by vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The disease is caused by variants affecting the gene represented in this entry. ACP5 inactivating mutations result in a functional excess of phosphorylated osteopontin causing deregulation of osteopontin signaling and consequential autoimmune disease.

Cofactor. Binds 2 iron ions per subunit.

Similarity. Belongs to the metallophosphoesterase superfamily. Purple acid phosphatase family.

RefSeq proteins (5): NP_001104504, NP_001104505, NP_001104506, NP_001308952, NP_001602* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004843	Calcineurin-like_PHP	Domain
IPR024927	Acid_PPase	Family
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR051558	Metallophosphoesterase_PAP	Family

Pfam: PF00149

Enzyme classification (BRENDA):

• EC 3.1.3.2 — acid phosphatase (BRENDA: 170 organisms, 858 substrates, 644 inhibitors, 497 Km, 138 kcat entries)

Substrate kinetics (BRENDA)

124 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
P-NITROPHENYL PHOSPHATE	0.0002–25	98
4-NITROPHENYL PHOSPHATE	—	84
ATP	0.066–30	22
PHENYL PHOSPHATE	0.16–17	15
PHOSPHOENOLPYRUVATE	0.05–2.1	12
ADP	0.1–8.7	11
1-NAPHTHYL PHOSPHATE	0.079–6.4	8
DIPHOSPHATE	0.08–4.6	8
4-METHYLUMBELLIFERYL PHOSPHATE	0.02–3.8	7
GTP	0.16–8.6	7
PHOSPHOTYROSINE	0.18–4.1	7
2-GLYCEROPHOSPHATE	0.4–66.7	6
3’-AMP	0.091–3.3	6
2-NAPHTHYL PHOSPHATE	0.13–4.5	5
5’-AMP	0.08–3.9	5

Catalyzed reactions (Rhea), 1 shown:

• a phosphate monoester + H2O = an alcohol + phosphate (RHEA:15017)

UniProt features (59 total): strand 15, sequence variant 12, helix 12, binding site 8, sequence conflict 5, glycosylation site 2, turn 2, signal peptide 1, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2BQ8	X-RAY DIFFRACTION	2.2
1WAR	X-RAY DIFFRACTION	2.22

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13686-F1	94.82	0.92

Functional residue map

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

Ligand- & substrate-binding residues (8): 33; 71; 71; 74; 110; 205; 240; 242

Disulfide bonds (1): 161–219

Glycosylation sites (2): 116, 147

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196843	Vitamin B2 (riboflavin) metabolism

MSigDB gene sets: 550 (showing top): KOBAYASHI_EGFR_SIGNALING_24HR_UP, MCLACHLAN_DENTAL_CARIES_UP, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, MODULE_418, GOBP_REGULATION_OF_SUPEROXIDE_ANION_GENERATION, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_SUPEROXIDE_METABOLIC_PROCESS, KEGG_LYSOSOME, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (14): nitric oxide biosynthetic process (GO:0006809), negative regulation of macrophage cytokine production (GO:0010936), response to lipopolysaccharide (GO:0032496), negative regulation of interleukin-1 beta production (GO:0032691), negative regulation of interleukin-12 production (GO:0032695), negative regulation of tumor necrosis factor production (GO:0032720), negative regulation of superoxide anion generation (GO:0032929), response to cytokine (GO:0034097), superoxide anion generation (GO:0042554), negative regulation of nitric oxide biosynthetic process (GO:0045019), bone resorption (GO:0045453), negative regulation of inflammatory response (GO:0050728), defense response to Gram-positive bacterium (GO:0050830), bone morphogenesis (GO:0060349)

GO Molecular Function (5): acid phosphatase activity (GO:0003993), ferrous iron binding (GO:0008198), ferric iron binding (GO:0008199), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): lysosome (GO:0005764), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
iron ion binding	2
cellular anatomical structure	2
biosynthetic process	1
nitric oxide metabolic process	1
negative regulation of cytokine production involved in immune response	1
macrophage cytokine production	1
regulation of macrophage cytokine production	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
negative regulation of interleukin-1 production	1
negative regulation of cytokine production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
regulation of superoxide anion generation	1
superoxide anion generation	1
negative regulation of reactive oxygen species metabolic process	1
response to peptide	1
superoxide metabolic process	1
nitric oxide biosynthetic process	1
negative regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
tissue homeostasis	1
bone remodeling	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
defense response to bacterium	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
phosphatase activity	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

2926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACP5	TNFSF11	O14788	962
ACP5	NFATC1	O95644	953
ACP5	CTSK	P43235	913
ACP5	BGLAP	P02818	882
ACP5	DCSTAMP	Q9H295	822
ACP5	FOS	P01100	810
ACP5	CALCR	P30988	795
ACP5	PTH	P01270	793
ACP5	TNFRSF11B	O00300	771
ACP5	OSCAR	Q8IYS5	769
ACP5	RUNX2	Q13950	762
ACP5	CSF1	P09603	728
ACP5	SOST	Q9BQB4	727
ACP5	ATP6V0D2	Q8N8Y2	720
ACP5	SP7	Q8TDD2	720

IntAct

19 interactions, top by confidence:

A	B	Type	Score
ACP5	KLHL15	psi-mi:“MI:0914”(association)	0.530
ZSCAN26	LRP4	psi-mi:“MI:0914”(association)	0.530
OGFOD3	CLGN	psi-mi:“MI:0914”(association)	0.530
TAS2R14	ACP5	psi-mi:“MI:0915”(physical association)	0.400
ACP5	IGF2R	psi-mi:“MI:0915”(physical association)	0.400
ACP5	PPP2CB	psi-mi:“MI:0915”(physical association)	0.370
HSD17B7	POLB	psi-mi:“MI:0914”(association)	0.350
ACP5	HSPA5	psi-mi:“MI:0914”(association)	0.350
ACP5	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MAPK9	ACP5	psi-mi:“MI:0915”(physical association)	0.000
ACP5	PDCD5	psi-mi:“MI:0915”(physical association)	0.000
ACP5	SLC35F6	psi-mi:“MI:0915”(physical association)	0.000
EGR2	ACP5	psi-mi:“MI:0915”(physical association)	0.000
RPA2	ACP5	psi-mi:“MI:0915”(physical association)	0.000
TNFSF10	ACP5	psi-mi:“MI:0915”(physical association)	0.000
ACP5	ZBTB16	psi-mi:“MI:0915”(physical association)	0.000
SNRNP40	ACP5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (38): HSPA5 (Affinity Capture-MS), KLHL15 (Affinity Capture-MS), CIZ1 (Affinity Capture-MS), ACP5 (Affinity Capture-MS), ACP5 (Affinity Capture-MS), CALR (Affinity Capture-MS), SEP15 (Affinity Capture-MS), UGGT1 (Affinity Capture-MS), CLGN (Affinity Capture-MS), COA7 (Affinity Capture-MS), OS9 (Affinity Capture-MS), PDIA3 (Affinity Capture-MS), CANX (Affinity Capture-MS), SEL1L (Affinity Capture-MS), P4HB (Affinity Capture-MS)

ESM2 similar proteins: A5D6U8, O23244, O48840, O97860, P06865, P07686, P08236, P09889, P13686, P20060, P29240, P29288, P29416, P49614, P80366, Q05117, Q0V8R6, Q38924, Q53F39, Q5MAU8, Q5R5N6, Q5RC84, Q5RET5, Q5RFI5, Q641X3, Q641Z7, Q687E1, Q6AYS4, Q6TPH1, Q6ZNF0, Q8BX37, Q8H1R2, Q8S340, Q8S341, Q8VYU7, Q8VYZ2, Q93WP4, Q949Y3, Q99KR8, Q9BTY2

Diamond homologs: O97860, P09889, P13686, P29288, Q05117, Q8VYZ2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MITF	“up-regulates quantity by expression”	ACP5	“transcriptional regulation”
SPI1	“up-regulates quantity by expression”	ACP5	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	3
Uncertain significance	164
Likely benign	120
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031092	NM_001611.5(ACP5):c.736-2A>G	Pathogenic
1072535	NC_000019.9:g.(?11685805)(11688152_?)del	Pathogenic
1073554	NM_001611.5(ACP5):c.733C>T (p.Gln245Ter)	Pathogenic
1075181	NM_001611.5(ACP5):c.257del (p.Phe86fs)	Pathogenic
1373515	NM_001611.5(ACP5):c.526del (p.Arg176fs)	Pathogenic
1375674	NM_001611.5(ACP5):c.259del (p.Gln87fs)	Pathogenic
1401166	NM_001611.5(ACP5):c.375_376insTA (p.Ile126Ter)	Pathogenic
1403982	NM_001611.5(ACP5):c.222C>A (p.Tyr74Ter)	Pathogenic
1437995	NM_001611.5(ACP5):c.136del (p.Arg46fs)	Pathogenic
1452268	NM_001611.5(ACP5):c.361del (p.Ile121fs)	Pathogenic
1452787	NM_001611.5(ACP5):c.266_272del (p.Thr89fs)	Pathogenic
1455117	NM_001611.5(ACP5):c.799del (p.Ser267fs)	Pathogenic
1456634	NM_001611.5(ACP5):c.712T>C (p.Cys238Arg)	Pathogenic
147761	GRCh38/hg38 19p13.2-13.12(chr19:11525163-14155021)x1	Pathogenic
1510689	NM_001611.5(ACP5):c.721G>A (p.Asp241Asn)	Pathogenic
153069	GRCh38/hg38 19p13.2-13.13(chr19:10319474-13777860)x1	Pathogenic
1897232	NM_001611.5(ACP5):c.372dup (p.Lys125Ter)	Pathogenic
2030290	NM_001611.5(ACP5):c.654_658del (p.Cys219fs)	Pathogenic
2110138	NM_001611.5(ACP5):c.628_634delinsCCTACC (p.Ser210fs)	Pathogenic
2134218	NM_001611.5(ACP5):c.550C>T (p.Gln184Ter)	Pathogenic
225658	NM_001611.5(ACP5):c.816dup (p.Lys273fs)	Pathogenic
2417776	NM_001611.5(ACP5):c.710_718del (p.Leu237_Gly239del)	Pathogenic
2423723	NC_000019.9:g.(?11685825)(11688132_?)del	Pathogenic
2736805	NM_001611.5(ACP5):c.618C>A (p.Tyr206Ter)	Pathogenic
2980611	NM_001611.5(ACP5):c.372_373insC (p.Lys125fs)	Pathogenic
29829	NM_001611.5(ACP5):c.266C>T (p.Thr89Ile)	Pathogenic
29830	NM_001611.5(ACP5):c.667C>T (p.Gln223Ter)	Pathogenic
29831	NM_001611.5(ACP5):c.791T>A (p.Met264Lys)	Pathogenic
29832	NM_001611.5(ACP5):c.643G>C (p.Gly215Arg)	Pathogenic
3062391	GRCh37/hg19 19p13.2(chr19:10441330-13077352)x1	Pathogenic

SpliceAI

872 predictions. Top by Δscore:

Variant	Effect	Δscore
19:11575248:AGGTA:A	acceptor_gain	1.0000
19:11575249:GGTA:G	acceptor_gain	1.0000
19:11575250:GTA:G	acceptor_gain	1.0000
19:11575251:TA:T	acceptor_gain	1.0000
19:11575252:ACTGA:A	acceptor_loss	1.0000
19:11575253:C:CC	acceptor_gain	1.0000
19:11575253:CTG:C	acceptor_loss	1.0000
19:11576238:CTCAC:C	donor_loss	1.0000
19:11576241:A:AC	donor_gain	1.0000
19:11576241:ACC:A	donor_loss	1.0000
19:11576242:C:A	donor_loss	1.0000
19:11576242:C:CC	donor_gain	1.0000
19:11576242:CCTG:C	donor_gain	1.0000
19:11576589:C:CC	acceptor_gain	1.0000
19:11577056:C:A	donor_loss	1.0000
19:11577316:ATCT:A	acceptor_loss	1.0000
19:11578838:TCTCA:T	donor_loss	1.0000
19:11578839:CTCA:C	donor_loss	1.0000
19:11578840:TCA:T	donor_loss	1.0000
19:11578841:CACCT:C	donor_loss	1.0000
19:11578842:A:T	donor_loss	1.0000
19:11575250:GTACT:G	acceptor_gain	0.9900
19:11575252:ACTG:A	acceptor_gain	0.9900
19:11575259:A:AC	acceptor_gain	0.9900
19:11576584:AGTTC:A	acceptor_gain	0.9900
19:11576585:GTTC:G	acceptor_gain	0.9900
19:11576586:TTC:T	acceptor_gain	0.9900
19:11576586:TTCC:T	acceptor_loss	0.9900
19:11576587:TC:T	acceptor_gain	0.9900
19:11576587:TCCT:T	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000097485 (19:11574477 A>G,T), RS1000152579 (19:11575559 CA>C,CAA), RS1000302308 (19:11574341 T>C), RS1000343516 (19:11580045 T>C), RS1000696096 (19:11578458 G>A), RS1001486618 (19:11580639 C>T), RS1001679250 (19:11575993 G>A,T), RS1002537286 (19:11574374 C>T), RS1002608374 (19:11575482 G>A), RS1002850948 (19:11575946 G>A), RS1002913361 (19:11578175 G>A), RS1002965804 (19:11577897 G>A,T), RS1003000312 (19:11579608 T>C), RS1003158734 (19:11579237 C>A), RS1003958403 (19:11578898 A>G)

Disease associations

OMIM: gene MIM:171640 | disease phenotypes: MIM:271550, MIM:607944, MIM:108500, MIM:231670, MIM:248500, MIM:606482, MIM:617106

GenCC curated gene-disease

Disease	Classification	Inheritance
Spondyloenchondrodysplasia with immune dysregulation	Definitive	Autosomal recessive

Mondo (6): Spondyloenchondrodysplasia with immune dysregulation (MONDO:0011939), episodic ataxia type 2 (MONDO:0007163), glutaryl-CoA dehydrogenase deficiency (MONDO:0009281), alpha-mannosidosis (MONDO:0009561), Charcot-Marie-Tooth disease dominant intermediate B (MONDO:0011674), developmental and epileptic encephalopathy, 42 (MONDO:0014917)

Orphanet (7): Spondyloenchondrodysplasia (Orphanet:1855), Autosomal dominant intermediate Charcot-Marie-Tooth disease type B (Orphanet:100044), Autosomal dominant Charcot-Marie-Tooth disease type 2M (Orphanet:228179), Glutaryl-CoA dehydrogenase deficiency (Orphanet:25), Alpha-mannosidosis (Orphanet:61), Familial paroxysmal ataxia (Orphanet:97), Spondylometaphyseal dysplasia with combined immunodeficiency (Orphanet:50816)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000262	Turricephaly
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000460	Narrow nose
HP:0000684	Delayed eruption of teeth
HP:0000689	Dental malocclusion
HP:0000707	Abnormality of the nervous system
HP:0000768	Pectus carinatum
HP:0000790	Hematuria
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000926	Platyspondyly
HP:0000946	Hypoplastic ilia
HP:0000979	Purpura
HP:0000988	Skin rash
HP:0001034	Hypermelanotic macule
HP:0001045	Vitiligo
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0001270	Motor delay
HP:0001369	Arthritis
HP:0001370	Rheumatoid arthritis
HP:0001386	Joint swelling

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000266_3	Multiple sclerosis (severity)	9.000000e-06
GCST006585_328	Blood protein levels	2.000000e-17

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008363	alpha-Mannosidosis	C16.320.565.202.607.500; C16.320.565.595.577.500; C18.452.648.202.607.500; C18.452.648.595.577.500
C564307	Combined Immunodeficiency with Autoimmunity and Spondylometaphyseal Dysplasia (supp.)
C535506	Episodic Ataxia, Type 2 (supp.)
C536833	Glutaric Acidemia I (supp.)
C535782	Spondyloenchondrodysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2229531	ACP5, ZNF627		0.00	0
rs2305799	ACP5, ZNF627		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	4
Benzo(a)pyrene	affects methylation, increases expression	3
maxacalcitol	decreases expression	2
entinostat	increases expression, affects cotreatment	2
Cisplatin	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
Aflatoxin B1	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression, increases secretion	1
belinostat	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Venlafaxine Hydrochloride	decreases expression	1
Resveratrol	affects cotreatment, decreases reaction, increases activity	1
Decitabine	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Aluminum Oxide	decreases expression	1
Beclomethasone	decreases activity	1
Calcitriol	decreases expression	1
Dactinomycin	affects cotreatment, increases expression, increases secretion	1
Dexamethasone	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07221292	PHASE3	NOT_YET_RECRUITING	Pivotal Study of N-acetyl-L-leucine for CACNA1A
NCT01681953	PHASE3	COMPLETED	A Placebo-Controlled Phase 3 Trial of Repeated Lamazym Treatment of Subjects With Alpha-Mannosidosis
NCT01908712	PHASE3	COMPLETED	Lamazym Aftercare Study FR Designed to Provide Treatment for French Patients
NCT01908725	PHASE3	COMPLETED	Lamazym Aftercare Study
NCT02478840	PHASE3	COMPLETED	Evaluation of Long-term Efficacy of Treatment With Lamazym
NCT04031066	PHASE3	WITHDRAWN	Interventional Study to Assess Efficacy and Safety of Velmanase Alfa in Patients With Alpha Mannosidosis
NCT01543750	PHASE2	WITHDRAWN	4-Aminopyridine in Episodic Ataxia Type 2
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01285700	PHASE2	UNKNOWN	Dose Finding Study of Recombinant Human Alpha-mannosidase for the Treatment of Patients With Alpha-mannosidosis
NCT01681940	PHASE2	COMPLETED	Long-term Efficacy and Safety of Lamazym for the Treatment of Patients With Alpha-Mannosidosis
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT02998879	PHASE2	COMPLETED	Trial on Safety and Efficacy of Velmanase Alfa Treatment in Pediatric Patients With Alpha-Mannosidosis
NCT06217861	PHASE1	RECRUITING	A Study to Evaluate the Tolerability, Safety and Efficacy of VGM-R02b
NCT01268358	PHASE1	COMPLETED	Safety Study of Recombinant Human Alpha-mannosidase for the Treatment of Patients With Alpha-mannosidosis
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT00498420	Not specified	COMPLETED	The Natural History of Alpha-Mannosidosis
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses
NCT02141503	Not specified	COMPLETED	Clinical Biomarkers in Alpha-mannosidosis
NCT03264040	Not specified	WITHDRAWN	Biomarker for Mannosidosis Disease (BioMannosidosis)
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT04959240	Not specified	AVAILABLE	Expanded Access to Velmanase Alfa
NCT06184503	Not specified	RECRUITING	Analysis of Velmanase Alfa (Lamzede®)’s Effects in the Body of Children With Alpha-Mannosidosis Under the Age 3