ASPH

Summary

ASPH (aspartate beta-hydroxylase, HGNC:757) is a protein-coding gene on chromosome 8q12.3, encoding Aspartyl/asparaginyl beta-hydroxylase (Q12797). Specifically hydroxylates an Asp or Asn residue in certain epidermal growth factor-like (EGF) domains of a number of proteins.

This gene is thought to play an important role in calcium homeostasis. The gene is expressed from two promoters and undergoes extensive alternative splicing. The encoded set of proteins share varying amounts of overlap near their N-termini but have substantial variations in their C-terminal domains resulting in distinct functional properties. The longest isoforms (a and f) include a C-terminal Aspartyl/Asparaginyl beta-hydroxylase domain that hydroxylates aspartic acid or asparagine residues in the epidermal growth factor (EGF)-like domains of some proteins, including protein C, coagulation factors VII, IX, and X, and the complement factors C1R and C1S. Other isoforms differ primarily in the C-terminal sequence and lack the hydroxylase domain, and some have been localized to the endoplasmic and sarcoplasmic reticulum. Some of these isoforms are found in complexes with calsequestrin, triadin, and the ryanodine receptor, and have been shown to regulate calcium release from the sarcoplasmic reticulum. Some isoforms have been implicated in metastasis.

Source: NCBI Gene 444 — RefSeq curated summary.

At a glance

• Gene–disease (curated): facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 320 total — 18 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes — 13 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_004318

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:757
Approved symbol	ASPH
Name	aspartate beta-hydroxylase
Location	8q12.3
Locus type	gene with protein product
Status	Approved
Aliases	CASQ2BP1, BAH, JCTN, HAAH
Ensembl gene	ENSG00000198363
Ensembl biotype	protein_coding
OMIM	600582
Entrez	444

Gene structure

Transcript identifiers

Ensembl transcripts: 110 — 101 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000356457, ENST00000379449, ENST00000379454, ENST00000389204, ENST00000445642, ENST00000517661, ENST00000517847, ENST00000517856, ENST00000517903, ENST00000517928, ENST00000518068, ENST00000518306, ENST00000518441, ENST00000519234, ENST00000519264, ENST00000519678, ENST00000520198, ENST00000521499, ENST00000521909, ENST00000522036, ENST00000522325, ENST00000522343, ENST00000522349, ENST00000522603, ENST00000522835, ENST00000522919, ENST00000523897, ENST00000523927, ENST00000524173, ENST00000541428, ENST00000887925, ENST00000887926, ENST00000887927, ENST00000887928, ENST00000887929, ENST00000887930, ENST00000887931, ENST00000887932, ENST00000887933, ENST00000887934, ENST00000887935, ENST00000887936, ENST00000887937, ENST00000887938, ENST00000887939, ENST00000887940, ENST00000887941, ENST00000887942, ENST00000887943, ENST00000887944, ENST00000887945, ENST00000887946, ENST00000887947, ENST00000887948, ENST00000887949, ENST00000887950, ENST00000887951, ENST00000887952, ENST00000887953, ENST00000887954, ENST00000887955, ENST00000887956, ENST00000887957, ENST00000887958, ENST00000887959, ENST00000887960, ENST00000887961, ENST00000887962, ENST00000887963, ENST00000887964, ENST00000887965, ENST00000887966, ENST00000887967, ENST00000887968, ENST00000887969, ENST00000887970, ENST00000887971, ENST00000887972, ENST00000887973, ENST00000887974, ENST00000887975, ENST00000887976, ENST00000913379, ENST00000913380, ENST00000913381, ENST00000913382, ENST00000913383, ENST00000950776, ENST00000950777, ENST00000950778, ENST00000950779, ENST00000950780, ENST00000950781, ENST00000950782, ENST00000950783, ENST00000950784, ENST00000950785, ENST00000950786, ENST00000950787, ENST00000950788, ENST00000950789, ENST00000950790, ENST00000950791, ENST00000950792, ENST00000950793, ENST00000950794, ENST00000950795, ENST00000950796, ENST00000950797, ENST00000950798

RefSeq mRNA: 77 — MANE Select: NM_004318 NM_001164750, NM_001164751, NM_001164752, NM_001164753, NM_001164754, NM_001164755, NM_001164756, NM_001413844, NM_001413845, NM_001413846, NM_001413847, NM_001413848, NM_001413849, NM_001413850, NM_001413851, NM_001413852, NM_001413853, NM_001413854, NM_001413855, NM_001413856, NM_001413857, NM_001413858, NM_001413859, NM_001413860, NM_001413861, NM_001413862, NM_001413863, NM_001413864, NM_001413865, NM_001413866, NM_001413867, NM_001413868, NM_001413869, NM_001413870, NM_001413871, NM_001413872, NM_001413873, NM_001413874, NM_001413875, NM_001413876, NM_001413877, NM_001413878, NM_001413879, NM_001413880, NM_001413881, NM_001413882, NM_001413883, NM_001413884, NM_001413885, NM_001413886, NM_001413887, NM_001413888, NM_001413889, NM_001413890, NM_001413891, NM_001413893, NM_001413894, NM_001413895, NM_001413896, NM_001413897, NM_001413898, NM_001413899, NM_001413900, NM_001413901, NM_001413902, NM_001413903, NM_001413904, NM_001413905, NM_001413906, NM_001413907, NM_001413908, NM_001413909, NM_004318, NM_020164, NM_032466, NM_032467, NM_032468

CCDS: CCDS34898, CCDS34899, CCDS34900, CCDS43742, CCDS47866, CCDS55234, CCDS55235, CCDS55236, CCDS55237, CCDS55238, CCDS75746

Canonical transcript exons

ENST00000379454 — 25 exons

Exon	Start	End
ENSE00001481101	61500556	61503509
ENSE00002102800	61714269	61714592
ENSE00003801365	61517528	61517661
ENSE00003802138	61646750	61646878
ENSE00003802642	61643386	61643433
ENSE00003803149	61562744	61562880
ENSE00003803310	61618978	61619019
ENSE00003803477	61651050	61651124
ENSE00003804214	61548071	61548208
ENSE00003804292	61684039	61684188
ENSE00003804713	61553031	61553120
ENSE00003804729	61567168	61567318
ENSE00003805760	61525977	61526112
ENSE00003806593	61518032	61518123
ENSE00003806662	61653568	61653660
ENSE00003807052	61644600	61644632
ENSE00003807820	61637947	61638003
ENSE00003807848	61643945	61644001
ENSE00003808270	61642888	61642920
ENSE00003809256	61555924	61556022
ENSE00003810324	61680968	61681036
ENSE00003810955	61633683	61633727
ENSE00003810995	61638322	61638363
ENSE00003811304	61576772	61576858
ENSE00003811382	61583944	61584029

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 165.4686 / max 2802.5444, expressed in 1818 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93293	146.7375	1817
93288	6.3364	355
93294	5.3812	1519
93279	1.6158	646
93284	1.4969	732
93283	1.3150	643
93287	0.9514	223
93280	0.8387	395
93277	0.7273	266
93271	0.0249	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.46	gold quality
stromal cell of endometrium	CL:0002255	99.15	gold quality
palpebral conjunctiva	UBERON:0001812	99.14	gold quality
colonic epithelium	UBERON:0000397	99.06	gold quality
adrenal tissue	UBERON:0018303	98.95	gold quality
tendon	UBERON:0000043	98.76	gold quality
islet of Langerhans	UBERON:0000006	98.61	gold quality
right adrenal gland cortex	UBERON:0035827	98.54	gold quality
left adrenal gland	UBERON:0001234	98.48	gold quality
germinal epithelium of ovary	UBERON:0001304	98.38	gold quality
left adrenal gland cortex	UBERON:0035825	98.36	gold quality
right adrenal gland	UBERON:0001233	98.33	gold quality
adrenal cortex	UBERON:0001235	98.26	gold quality
adrenal gland	UBERON:0002369	98.25	gold quality
adipose tissue	UBERON:0001013	98.19	gold quality
choroid plexus epithelium	UBERON:0003911	98.11	gold quality
tongue squamous epithelium	UBERON:0006919	98.08	gold quality
thoracic mammary gland	UBERON:0005200	97.97	gold quality
mammary gland	UBERON:0001911	97.95	gold quality
synovial joint	UBERON:0002217	97.94	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.91	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.86	gold quality
ventricular zone	UBERON:0003053	97.83	gold quality
omental fat pad	UBERON:0010414	97.83	gold quality
peritoneum	UBERON:0002358	97.81	gold quality
connective tissue	UBERON:0002384	97.81	gold quality
sural nerve	UBERON:0015488	97.78	gold quality
gastrocnemius	UBERON:0001388	97.74	gold quality
muscle of leg	UBERON:0001383	97.66	gold quality
tibia	UBERON:0000979	97.60	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	1551.67
E-HCAD-35	yes	69.25
E-GEOD-125970	yes	20.31
E-GEOD-84465	yes	11.27
E-GEOD-130148	yes	9.50
E-GEOD-124858	no	990.19
E-MTAB-6108	no	228.61
E-HCAD-31	no	20.81
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2A, NOTCH3, SP1, SP3, USF1, USF2

miRNA regulators (miRDB)

157 targeting ASPH, 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-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• role of gene in neuroblastoma cell motility (PMID:12118090)
• AAH over-expression may contribute to the infiltrative growth pattern of cholangiocarcinoma cells by promoting motility. (PMID:12713872)
• junctate has a role in calcium homeostasis in eukaryotic cells (PMID:15302852)
• This review summarizes recent progress in elucidating the molecular mechanisms of hypoxia-inducible factor (HIF)-1 activation, focusing on the role of oxygen-dependent prolyl hydroxylase in hypoxia signal transduction. (PMID:16154531)
• Overexpression of aspartyl beta-hydroxylase plays a role in the development and progression of hepatocellular carcinoma. (PMID:16341145)
• enhanced AAH gene activity is a common feature of human hepatocellular carcinoma and growth factor signaling through IRS-1 regulates AAH expression and increases cell motility and invasion (PMID:16564107)
• Human aspartyl (asparaginyl) beta-hydroxylase (HAAH) mRNA is overexpressed in biliary cancer cell lines and possibly involved in the pathogenesis of bile duct cancer. (PMID:16673309)
• Abundant AAH expression in trophoblasts as well as in decidua and endometrial glands, with reduced expression in spontaneous abortion and small-for-gestational-age term deliveries, suggesting that AAH may serve as a biomarker of impaired implantation. (PMID:16949909)
• Study demonstrates that high levels of humbug immunoreactivity in colon carcinomas correlate with histologic grade and tumor behavior, suggesting that humbug can serve as a prognostic biomarker. (PMID:17020779)
• AAH and Humbug are over-expressed in SH-Sy5y neuroblastoma cells, and their mRNAs are regulated by insulin/IGF-1 signaling through Erk MAPK, PI3 kinase-Akt, and Cdk-5, which are known mediators of cell migration. (PMID:17156427)
• Expression analysis showed that the mRNA expression level of humbug was correlated with invasive potential in various human gastric cancer cell lines. (PMID:18288418)
• USF1 and USF2 positively regulate the core of P1 promoter od AAH. (PMID:19087304)
• Low expression of AAH in the endochylema and nucleus of trephocyte may play a role in patients with missed abortion. (PMID:19197126)
• High levels of aspartyl (asparaginyl)-beta-hydroxylase/humbug correlate with poor prognosis in non-small cell lung cancer, particularly squamous cell carcinoma subtype. (PMID:19200576)
• analysis of aspartyl (asparaginyl) beta-hydroxylase monoclonal antibodies (PMID:19663697)
• Aspartyl-asparaginyl-beta-hydroxylase is an important, positive regulator of trophoblastic cell motility, and it’s inhibition in vivo leads to impaired implantation and fetal growth, and alters Notch-signaling mechanisms. (PMID:21862239)
• Ca(2+) and JNT-dependent disassembly of the CSQ2 polymer (PMID:22123818)
• Data show that junctate (ASPH) is an interacting partner of Orai1-STIM1 complex. (PMID:22586105)
• this study provides evidence that ASPH is mutated in a distinct form of syndromic ectopia lentis. (PMID:24768550)
• Higher levels of HAAH/humbug mRNA were found in the hepatocellular carcinoma tissues relative to the adjacent cancerfree tissue. (PMID:25394783)
• the role of FTH1 in the FIH control of HIF-1 activity, is reported. (PMID:29580991)
• Expression of aspartate beta-hydroxylase (ASPH) promoted direct protein interaction between RB1, cyclin-dependent kinases, and cyclins. (PMID:29733964)
• The mRNA expression and promoter methylation rate of ASPH gene may play a role in the development and progression of breast cancer. (PMID:29737090)
• the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC. (PMID:29764768)
• We report the 14th individual with Traboulsi syndrome and a novel homozygous deletion variant in exon 22 of ASPH gene associated with the phenotype. (PMID:31012784)
• An unexpected Cys3-4 disulfide bonding pattern is observed in the epidermal growth factor-like domains of AspH. (PMID:31659163)
• ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy. (PMID:31694640)
• High ASPH expression is associated with pancreatic ductal adenocarcinoma metastasisthrough activation of SRC signaling pathway. (PMID:31888763)
• Kinetic parameters of human aspartate/asparagine-beta-hydroxylase suggest that it has a possible function in oxygen sensing. (PMID:32107312)
• Aspartate beta-hydroxylase targeting in castration-resistant prostate cancer modulates the NOTCH/HIF1alpha/GSK3beta crosstalk. (PMID:32525968)
• Diverse molecular functions of aspartate betahydroxylase in cancer (Review). (PMID:33125119)
• A novel mutation in the aspartate beta-hydroxylase (ASPH) gene is associated with a rare form of Traboulsi syndrome. (PMID:33251883)
• Characterization of the Relationship Between the Expression of Aspartate beta-Hydroxylase and the Pathological Characteristics of Breast Cancer. (PMID:33380715)
• Human Oxygenase Variants Employing a Single Protein Fe(II) Ligand Are Catalytically Active. (PMID:33887099)
• Expanding the clinical spectrum and management of Traboulsi syndrome: report on two siblings homozygous for a novel pathogenic variant in ASPH. (PMID:34018898)
• Overexpression of Human Aspartyl (Asparaginyl) beta-hydroxylase in NSCLC: Its Diagnostic Value by Means of Exosomes of Bronchoalveolar Lavage. (PMID:34433181)
• Traboulsi syndrome caused by mutations in ASPH: An autosomal recessive disorder with overlapping features of Marfan syndrome. (PMID:35918038)
• Overexpression of ASPH protein predicts poor outcomes in retroperitoneal liposarcoma patients. (PMID:36897757)
• Aspartate beta-hydroxylase (ASPH) Accelerates Intrahepatic Cholangiocarcinoma Metastasis via Upregulating SHH Signaling Pathway. (PMID:37132101)
• Genotype-phenotype profile of global ASPH-associated ectopia lentis and clinical findings from a Chinese cohort. (PMID:38788814)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	unm_hu7910	ENSDARG00000078703
mus_musculus	Asph	ENSMUSG00000028207
rattus_norvegicus	Asph	ENSRNOG00000007445
drosophila_melanogaster	Asph	FBGN0034075
caenorhabditis_elegans		WBGENE00010703

Paralogs (2): ASPHD2 (ENSG00000128203), ASPHD1 (ENSG00000174939)

Protein

Protein identifiers

Aspartyl/asparaginyl beta-hydroxylase — Q12797 (reviewed: Q12797)

Alternative names: Aspartate beta-hydroxylase, Peptide-aspartate beta-dioxygenase

All UniProt accessions (11): A0A087WUJ2, A0A087WW05, A0A087WW51, A0A087X0J4, E5RG29, E5RG56, E5RHJ2, E5RHK2, E5RJL3, Q12797, G3XAN5

UniProt curated annotations — full annotation on UniProt →

Function. Specifically hydroxylates an Asp or Asn residue in certain epidermal growth factor-like (EGF) domains of a number of proteins. Membrane-bound Ca(2+)-sensing protein, which is a structural component of the ER-plasma membrane junctions. Isoform 8 regulates the activity of Ca(+2) released-activated Ca(+2) (CRAC) channels in T-cells.

Subunit / interactions. Monomer. Isoform 8 interacts with ORAI1 and STIM1. Isoform 4 interacts with CASQ2.

Subcellular location. Endoplasmic reticulum membrane Sarcoplasmic reticulum membrane Endoplasmic reticulum membrane.

Tissue specificity. Isoform 1 is detected in all tissues tested. Isoform 8 is mainly expressed in pancreas, heart, brain, kidney and liver. Isoform 8 is expressed in kidney (at protein level).

Disease relevance. Facial dysmorphism, lens dislocation, anterior segment abnormalities, and spontaneous filtering blebs (FDLAB) [MIM:601552] A syndrome characterized by dislocated crystalline lenses and anterior segment abnormalities in association with a distinctive facies involving flat cheeks and a beaked nose. Some affected individuals develop highly unusual non-traumatic conjunctival cysts (filtering blebs). The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the aspartyl/asparaginyl beta-hydroxylase family.

Isoforms (11)

UniProt ID	Names	Canonical?
Q12797-1	1	yes
Q12797-2	2
Q12797-3	3, Junctin-1, Cardiac junctin
Q12797-4	4, Junctin-2, Junctin
Q12797-5	5
Q12797-10	10
Q12797-6	6
Q12797-7	7
Q12797-8	8, Junctate
Q12797-9	9
Q12797-11	11

RefSeq proteins (77): NP_001158222, NP_001158223, NP_001158224, NP_001158225, NP_001158226, NP_001158227, NP_001158228, NP_001400773, NP_001400774, NP_001400775, NP_001400776, NP_001400777, NP_001400778, NP_001400779, NP_001400780, NP_001400781, NP_001400782, NP_001400783, NP_001400784, NP_001400785, NP_001400786, NP_001400787, NP_001400788, NP_001400789, NP_001400790, NP_001400791, NP_001400792, NP_001400793, NP_001400794, NP_001400795, NP_001400796, NP_001400797, NP_001400798, NP_001400799, NP_001400800, NP_001400801, NP_001400802, NP_001400803, NP_001400804, NP_001400805, NP_001400806, NP_001400807, NP_001400808, NP_001400809, NP_001400810, NP_001400811, NP_001400812, NP_001400813, NP_001400814, NP_001400815, NP_001400816, NP_001400817, NP_001400818, NP_001400819, NP_001400820, NP_001400822, NP_001400823, NP_001400824, NP_001400825, NP_001400826, NP_001400827, NP_001400828, NP_001400829, NP_001400830, NP_001400831, NP_001400832, NP_001400833, NP_001400834, NP_001400835, NP_001400836, NP_001400837, NP_001400838, NP_004309, NP_064549, NP_115855, NP_115856, NP_115857 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007803	Asp/Arg/Pro-Hydrxlase	Domain
IPR007943	Asp-B-hydro/Triadin_dom	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR027443	IPNS-like_sf	Homologous_superfamily
IPR039038	ASPH	Family

Pfam: PF05118, PF05279, PF13432

Enzyme classification (BRENDA):

• EC 1.14.11.16 — peptide-aspartate beta-dioxygenase (BRENDA: 4 organisms, 27 substrates, 85 inhibitors, 25 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.0006–0.125	8
FE2+	0.003–0.093	6
FIRST GROWTH FACTOR-LIKE DOMAIN-L-ASPARTATE	0.019–0.075	6
O2	0.09–0.426	2
HIF-1ALPHA PEPTIDE ASP788-LEU822 (L-ASPARAGINE8	0.1	1
[FACTOR X FIRST EGF-LIKE DOMAIN]-L-ASPARTATE	0.086	1
[THIOETHER-LINKED CYCLIC PEPTIDE HFX-CP101-119]-	0.0012	1

Catalyzed reactions (Rhea), 1 shown:

• L-aspartyl-[protein] + 2-oxoglutarate + O2 = 3-hydroxy-L-aspartyl-[protein] + succinate + CO2 (RHEA:11508)

UniProt features (87 total): helix 21, strand 15, binding site 11, splice variant 11, sequence conflict 7, repeat 4, region of interest 3, glycosylation site 3, topological domain 2, compositionally biased region 2, sequence variant 2, chain 1, transmembrane region 1, modified residue 1, disulfide bond 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6YYX	X-RAY DIFFRACTION	1.53
7YB9	X-RAY DIFFRACTION	1.54
9FVV	X-RAY DIFFRACTION	1.6
6Q9F	X-RAY DIFFRACTION	1.63
7BMI	X-RAY DIFFRACTION	1.66
7YBB	X-RAY DIFFRACTION	1.68
8RE5	X-RAY DIFFRACTION	1.7
9FVU	X-RAY DIFFRACTION	1.7
7BMJ	X-RAY DIFFRACTION	1.75
6YYV	X-RAY DIFFRACTION	1.77
6Z6Q	X-RAY DIFFRACTION	1.81
9HO2	X-RAY DIFFRACTION	1.83
7YBC	X-RAY DIFFRACTION	1.84
8RE9	X-RAY DIFFRACTION	1.84
8RE8	X-RAY DIFFRACTION	1.85
9HO1	X-RAY DIFFRACTION	1.85
6Q9I	X-RAY DIFFRACTION	1.85
7YBA	X-RAY DIFFRACTION	1.86
7E6J	X-RAY DIFFRACTION	1.9
9FVW	X-RAY DIFFRACTION	1.9
9FVX	X-RAY DIFFRACTION	1.9
9FVY	X-RAY DIFFRACTION	1.9
8RE6	X-RAY DIFFRACTION	1.92
8RE7	X-RAY DIFFRACTION	1.95
9FW0	X-RAY DIFFRACTION	1.95
7YB8	X-RAY DIFFRACTION	1.98
9FVZ	X-RAY DIFFRACTION	1.98
5JQY	X-RAY DIFFRACTION	1.99
5APA	X-RAY DIFFRACTION	2.05
5JZ8	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12797-F1	72.34	0.56

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 (11): 91; 93; 95; 97; 102; 625; 668; 679; 688–690; 725; 735

Post-translational modifications (1): 14

Disulfide bonds (1): 641–648

Glycosylation sites (3): 452, 706, 64

Mutagenesis-validated functional residues (1):

Position	Phenotype
91–93	increase in cytoplasmic ca(2+) via activation of endogenous crac channels.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-5578775	Ion homeostasis
R-HSA-9629569	Protein hydroxylation
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction
R-HSA-597592	Post-translational protein modification
R-HSA-983712	Ion channel transport

MSigDB gene sets: 582 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, WENDT_COHESIN_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, AAGCAAT_MIR137, GOBP_BODY_MORPHOGENESIS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATION_CHANNEL_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, RORA1_01, FISCHER_G1_S_CELL_CYCLE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN

GO Biological Process (26): detection of calcium ion (GO:0005513), muscle contraction (GO:0006936), pattern specification process (GO:0007389), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), positive regulation of calcium ion transport into cytosol (GO:0010524), regulation of cell communication by electrical coupling (GO:0010649), regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), obsolete regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity (GO:0031585), regulation of protein stability (GO:0031647), activation of store-operated calcium channel activity (GO:0032237), response to ATP (GO:0033198), limb morphogenesis (GO:0035108), positive regulation of proteolysis (GO:0045862), positive regulation of DNA-templated transcription (GO:0045893), regulation of cytosolic calcium ion concentration (GO:0051480), calcium ion homeostasis (GO:0055074), roof of mouth development (GO:0060021), face morphogenesis (GO:0060325), calcium ion transmembrane transport (GO:0070588), cellular response to calcium ion (GO:0071277), positive regulation of intracellular protein transport (GO:0090316), regulation of protein depolymerization (GO:1901879), peptidyl-amino acid modification (GO:0018193), peptidyl-aspartic acid hydroxylation (GO:0042264)

GO Molecular Function (10): structural molecule activity (GO:0005198), calcium ion binding (GO:0005509), structural constituent of muscle (GO:0008307), electron transfer activity (GO:0009055), transmembrane transporter binding (GO:0044325), peptidyl-aspartic acid 3-dioxygenase activity (GO:0062101), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (11): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), junctional sarcoplasmic reticulum membrane (GO:0014701), cortical endoplasmic reticulum (GO:0032541), sarcoplasmic reticulum membrane (GO:0033017), sarcoplasmic reticulum lumen (GO:0033018), calcium channel complex (GO:0034704), cytoplasm (GO:0005737), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Ion channel transport	1
Cardiac conduction	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Post-translational protein modification	1
Muscle contraction	1
Metabolism of proteins	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
molecular_function	2
sarcoplasmic reticulum	2
cellular anatomical structure	2
detection of chemical stimulus	1
response to calcium ion	1
muscle system process	1
multicellular organism development	1
multicellular organismal process	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
positive regulation of cytosolic calcium ion concentration	1
regulation of calcium ion transport into cytosol	1
calcium ion transport into cytosol	1
positive regulation of calcium ion transmembrane transport	1
cell communication by electrical coupling	1
regulation of cell communication	1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of release of sequestered calcium ion into cytosol	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
regulation of biological quality	1
positive regulation of store-operated calcium channel activity	1
response to purine-containing compound	1
response to organophosphorus	1
response to oxygen-containing compound	1
appendage morphogenesis	1
limb development	1
proteolysis	1
regulation of proteolysis	1
positive regulation of protein metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
intracellular calcium ion homeostasis	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
anatomical structure development	1
anatomical structure morphogenesis	1

Protein interactions and networks

STRING

1280 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASPH	TRDN	Q13061	999
ASPH	RYR2	Q92736	993
ASPH	CASQ1	P31415	982
ASPH	CASQ2	O14958	980
ASPH	FKBP1B	P68106	907
ASPH	JPH1	Q9HDC5	821
ASPH	CALM1	P02593	811
ASPH	MTA3	Q9BTC8	807
ASPH	JPH4	Q96JJ6	776
ASPH	RYR1	P21817	760
ASPH	CALML6	Q8TD86	755
ASPH	CALML3	P27482	754
ASPH	CALML4	Q96GE6	754
ASPH	CALML5	Q9NZT1	754
ASPH	JPH2	Q9BR39	742

IntAct

156 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
OLFM1	OLFM2	psi-mi:“MI:0914”(association)	0.640
AQP7	PLIN1	psi-mi:“MI:0914”(association)	0.570
GET3	ASPH	psi-mi:“MI:0915”(physical association)	0.560
ASPH	GET3	psi-mi:“MI:0915”(physical association)	0.560
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
SERPINA12	TSPAN6	psi-mi:“MI:0914”(association)	0.530
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
CD93	RARS1	psi-mi:“MI:0914”(association)	0.530
SIGMAR1	NPC1	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
	ASPH	psi-mi:“MI:0915”(physical association)	0.480
HTT	ASPH	psi-mi:“MI:0915”(physical association)	0.400
ASPH	CHRM5	psi-mi:“MI:0915”(physical association)	0.370
ECE1	ASPH	psi-mi:“MI:0915”(physical association)	0.370
PDGFRL	ASPH	psi-mi:“MI:0915”(physical association)	0.370
TK	AP3B1	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	IPO5	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (430): ASPH (Two-hybrid), ASPH (Affinity Capture-MS), ASPH (Affinity Capture-MS), ASPH (Affinity Capture-MS), ASPH (Affinity Capture-MS), ASPH (Affinity Capture-MS), ASPH (Co-fractionation), ASPH (Proximity Label-MS), CCDC109B (Affinity Capture-MS), MCU (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), FAM162A (Affinity Capture-MS), TMEM160 (Affinity Capture-MS), STX4 (Affinity Capture-MS), ASPH (Affinity Capture-MS)

ESM2 similar proteins: A2WNF5, I1HNB2, O08795, O23144, O73683, O93279, P05067, P08592, P0CT24, P12023, P14314, P14599, P15943, P53601, P79307, Q06335, Q06481, Q10651, Q12797, Q16891, Q28034, Q28056, Q498F0, Q4IEA7, Q4WCG2, Q5BDB9, Q5IS80, Q5JSH3, Q5NBP9, Q5TUF1, Q5XIN3, Q5ZM60, Q60495, Q6QD51, Q76M96, Q7KRW8, Q872S3, Q8AXP2, Q8BSY0, Q8CAQ8

Diamond homologs: A0JMH0, A1L515, B5DE73, Q12797, Q28056, Q2TA57, Q4VFY5, Q5HZW3, Q5U4P2, Q6ICH7, Q80VP9, Q8BSY0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 189 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	9	10.3×	3e-04
positive regulation of protein localization to plasma membrane	6	10.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	12
Uncertain significance	108
Likely benign	62
Benign	63

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1210220	NM_004318.4(ASPH):c.1782G>A (p.Trp594Ter)	Pathogenic
137614	NM_004318.4(ASPH):c.1852_1856delinsGGG (p.Asn618fs)	Pathogenic
1426171	NM_004318.4(ASPH):c.1916dup (p.Asn639fs)	Pathogenic
148601	GRCh38/hg38 8q12.1-12.3(chr8:55315854-64952752)x3	Pathogenic
155115	GRCh38/hg38 8q11.23-12.3(chr8:53325389-61863018)x1	Pathogenic
1683484	NM_004318.4(ASPH):c.322+12720A>C	Pathogenic
1683485	NM_004318.4(ASPH):c.323-11779G>C	Pathogenic
1915255	NM_004318.4(ASPH):c.1892G>A (p.Trp631Ter)	Pathogenic
2429371	NM_004318.4(ASPH):c.1394del (p.Leu465fs)	Pathogenic
2580343	GRCh37/hg19 8q12.1-12.3(chr8:61121294-63502403)x1	Pathogenic
2768808	NM_004318.4(ASPH):c.1482T>A (p.Tyr494Ter)	Pathogenic
3245489	NC_000008.10:g.(?61653992)(62626930_?)del	Pathogenic
3776052	NM_004318.4(ASPH):c.1552G>T (p.Gly518Ter)	Pathogenic
3900997	NM_004318.4(ASPH):c.1724G>A (p.Trp575Ter)	Pathogenic
4531227	NM_004318.4(ASPH):c.1910del (p.Asn637fs)	Pathogenic
60363	GRCh38/hg38 8q12.1-12.3(chr8:56925812-61691859)x1	Pathogenic
623642	NM_004318.4(ASPH):c.171G>A (p.Trp57Ter)	Pathogenic
689195	GRCh37/hg19 8q12.3(chr8:62449005-62474645)x1	Pathogenic
1210559	NM_004318.4(ASPH):c.1771G>T (p.Glu591Ter)	Likely pathogenic
137615	NM_004318.4(ASPH):c.2203C>T (p.Arg735Trp)	Likely pathogenic
1691259	NM_004318.4(ASPH):c.1626G>A (p.Glu542=)	Likely pathogenic
2425062	NC_000008.10:g.(?62460610)(62465699_?)del	Likely pathogenic
2860956	NM_004318.4(ASPH):c.1149+1G>A	Likely pathogenic
3065095	NM_004318.4(ASPH):c.1680G>A (p.Trp560Ter)	Likely pathogenic
3383478	NM_004318.4(ASPH):c.2160del (p.Asp720fs)	Likely pathogenic
3779356	NM_004318.4(ASPH):c.1171_1175del (p.Lys391fs)	Likely pathogenic
3900998	NM_004318.4(ASPH):c.1747del (p.Tyr583fs)	Likely pathogenic
4278250	NM_004318.4(ASPH):c.1150-1G>A	Likely pathogenic
4845927	NM_004318.4(ASPH):c.1764+1G>C	Likely pathogenic
977789	GRCh37/hg19 8q12.1-12.3(chr8:60026663-63779735)	Likely pathogenic

SpliceAI

5856 predictions. Top by Δscore:

Variant	Effect	Δscore
8:61517484:AT:A	donor_gain	1.0000
8:61555918:CATTA:C	donor_loss	1.0000
8:61555919:ATTAC:A	donor_loss	1.0000
8:61555920:TTAC:T	donor_loss	1.0000
8:61555921:TA:T	donor_loss	1.0000
8:61555923:C:CA	donor_loss	1.0000
8:61556021:ACC:A	acceptor_loss	1.0000
8:61562897:T:C	acceptor_gain	1.0000
8:61567317:CA:C	acceptor_gain	1.0000
8:61567319:C:CC	acceptor_gain	1.0000
8:61583942:AC:A	donor_gain	1.0000
8:61583943:CC:C	donor_gain	1.0000
8:61584025:CTTAA:C	acceptor_gain	1.0000
8:61584030:C:CC	acceptor_gain	1.0000
8:61619019:TCTGA:T	acceptor_loss	1.0000
8:61619020:C:A	acceptor_loss	1.0000
8:61619020:C:CC	acceptor_gain	1.0000
8:61619021:T:A	acceptor_loss	1.0000
8:61626154:T:TA	donor_gain	1.0000
8:61626158:T:TA	donor_gain	1.0000
8:61626159:C:A	donor_gain	1.0000
8:61633728:C:CC	acceptor_gain	1.0000
8:61638004:C:CC	acceptor_gain	1.0000
8:61643378:T:C	donor_gain	1.0000
8:61643434:C:CC	acceptor_gain	1.0000
8:61644002:C:CC	acceptor_gain	1.0000
8:61644598:ACCTG:A	donor_loss	1.0000
8:61644599:CCTGT:C	donor_gain	1.0000
8:61644630:TTT:T	acceptor_gain	1.0000
8:61644631:TTCTG:T	acceptor_loss	1.0000

AlphaMissense

5019 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:61503396:A:G	L747P	1.000
8:61503409:A:G	W743R	1.000
8:61503409:A:T	W743R	1.000
8:61503415:C:G	D741H	1.000
8:61503471:G:A	S722F	1.000
8:61503472:A:G	S722P	1.000
8:61503474:T:A	D721V	1.000
8:61503474:T:G	D721A	1.000
8:61503475:C:G	D721H	1.000
8:61503477:T:A	D720V	1.000
8:61517597:C:A	R686M	1.000
8:61517597:C:G	R686T	1.000
8:61517602:G:C	N684K	1.000
8:61517602:G:T	N684K	1.000
8:61517612:C:T	G681E	1.000
8:61517613:C:G	G681R	1.000
8:61517613:C:T	G681R	1.000
8:61517617:G:C	H679Q	1.000
8:61517617:G:T	H679Q	1.000
8:61517619:G:C	H679D	1.000
8:61518046:A:G	C660R	1.000
8:61526002:C:A	W625C	1.000
8:61526002:C:G	W625C	1.000
8:61526004:A:G	W625R	1.000
8:61526004:A:T	W625R	1.000
8:61526021:A:G	L619P	1.000
8:61548151:G:T	R562S	1.000
8:61553063:C:A	G532W	1.000
8:61684093:A:G	W67R	1.000
8:61684093:A:T	W67R	1.000

dbSNP variants (sampled 300 via entrez): RS1000009920 (8:61621289 T>C), RS1000020692 (8:61578180 C>T), RS1000024817 (8:61547419 C>A), RS1000029506 (8:61535096 C>A), RS1000056216 (8:61664862 C>G), RS1000056968 (8:61668745 A>G), RS1000064207 (8:61642321 A>G), RS1000081159 (8:61572126 G>A), RS1000097465 (8:61686124 T>C), RS1000114764 (8:61540914 G>A,T), RS1000133845 (8:61682503 T>A,C), RS1000166913 (8:61540640 C>T), RS1000171390 (8:61613023 T>C), RS1000172477 (8:61715600 C>T), RS1000189009 (8:61586405 A>C,G)

Disease associations

OMIM: gene MIM:600582 | disease phenotypes: MIM:601552

GenCC curated gene-disease

Disease	Classification	Inheritance
facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome	Strong	Autosomal recessive
malignant hyperthermia of anesthesia	Moderate	Autosomal dominant

Mondo (4): facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (MONDO:0011106), malignant hyperthermia of anesthesia (MONDO:0018493), exercise-induced malignant hyperthermia (MONDO:0018752), CHARGE syndrome (MONDO:0008965)

Orphanet (4): Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (Orphanet:412022), Malignant hyperthermia of anesthesia (Orphanet:423), Exercise-induced malignant hyperthermia (Orphanet:466650), CHARGE syndrome (Orphanet:138)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000324	Facial asymmetry
HP:0000426	Prominent nasal bridge
HP:0000444	Convex nasal ridge
HP:0000445	Wide nose
HP:0000448	Prominent nose
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000594	Shallow anterior chamber
HP:0000689	Dental malocclusion
HP:0000767	Pectus excavatum
HP:0001083	Ectopia lentis
HP:0001089	Iris atrophy
HP:0001132	Lens subluxation
HP:0001166	Arachnodactyly
HP:0001382	Joint hypermobility
HP:0001763	Pes planus
HP:0002156	Homocystinuria
HP:0002967	Cubitus valgus
HP:0007663	Reduced visual acuity
HP:0007906	Ocular hypertension
HP:0009381	Short finger
HP:0010055	Broad hallux

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002829_15	Urate levels in overweight individuals	4.000000e-06
GCST004213_4	Resting heart rate	2.000000e-08
GCST006585_1303	Blood protein levels	4.000000e-18
GCST006719_5	BRCA1/2-negative high-risk breast cancer	8.000000e-07
GCST010314_1	Serum omega-6 to omega-3 polyunsaturated fatty acid ratio in metabolic syndrome	7.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009443	BRCAX breast cancer
EFO:0010732	omega-6:omega-3 polyunsaturated fatty acid ratio

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058747	CHARGE Syndrome	C09.218.458.341.186.500.250; C10.597.751.418.341.186.500.250; C10.597.751.941.162.625.250; C11.270.147.500; C11.966.075.375.250; C16.131.077.299.250; C16.320.165; C23.888.592.763.393.341.186.500.500; C23.888.592.763.941.162.625.500
D008305	Malignant Hyperthermia	C23.550.505.700; C23.550.767.600; C23.888.119.455.500
C563293	Ectopia Lentis, Spontaneous Filtering Blebs, and Craniofacial Dysmorphism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4680030 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

13 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 65,436 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL2338329	ROXADUSTAT	4	1,063
CHEMBL3137309	VENETOCLAX	4	9,389
CHEMBL3544988	DAPRODUSTAT	4	308
CHEMBL3646221	VADADUSTAT	4	533
CHEMBL408513	BELINOSTAT	4	7,765
CHEMBL6067492	BLEOMYCIN	4
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL4297619	ENARODUSTAT	3	109
CHEMBL443684	NAVITOCLAX	3	4,791
CHEMBL4650314	DESIDUSTAT	3	254
CHEMBL51483	GOSSYPOL	3	13,973
CHEMBL376408	ABT 737	1	4,288

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4379440	Efficacy	3	warfarin

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4379440	ASPH	3	0.00	1	warfarin

ChEMBL bioactivities

64 potent at pChembl≥5 of 85 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	IC50	20	nM	CHEMBL316034
7.52	IC50	30	nM	CHEMBL316034
7.30	IC50	50	nM	CHEMBL5422782
7.00	IC50	100	nM	CHEMBL316034
6.96	IC50	110	nM	CHEMBL5430087
6.64	Kd	227.2	nM	CHEMBL3752910
6.64	ED50	227.2	nM	CHEMBL3752910
6.60	IC50	250	nM	GOSSYPOL
6.58	IC50	260	nM	GOSSYPOL
6.55	IC50	280	nM	CHEMBL5429223
6.48	IC50	330	nM	GOSSYPOL
6.30	IC50	500	nM	CHEMBL5425339
6.24	IC50	580	nM	CHEMBL5415306
6.10	IC50	800	nM	NAVITOCLAX
6.05	IC50	900	nM	CHEMBL5428941
5.99	IC50	1030	nM	NAVITOCLAX
5.92	IC50	1210	nM	NAVITOCLAX
5.92	IC50	1200	nM	CHEMBL5407378
5.91	IC50	1220	nM	CHEMBL5429166
5.89	IC50	1290	nM	VENETOCLAX
5.88	IC50	1330	nM	NAVITOCLAX
5.85	IC50	1400	nM	VENETOCLAX
5.83	IC50	1470	nM	BLEOMYCIN
5.82	IC50	1520	nM	VENETOCLAX
5.80	IC50	1570	nM	VENETOCLAX
5.78	IC50	1650	nM	BLEOMYCIN
5.75	IC50	1800	nM	CHEMBL5434665
5.73	IC50	1860	nM	CHEMBL5423241
5.72	IC50	1900	nM	CHEMBL5419332
5.70	IC50	1990	nM	BLEOMYCIN
5.70	IC50	2000	nM	CHEMBL5396670
5.64	IC50	2300	nM	CHEMBL6148285
5.60	IC50	2500	nM	CHEMBL6173707
5.58	IC50	2600	nM	CHEMBL5423565
5.55	IC50	2800	nM	CHEMBL5402035
5.54	IC50	2920	nM	ABT 737
5.52	IC50	2990	nM	ABT 737
5.51	IC50	3100	nM	BELINOSTAT
5.47	IC50	3380	nM	ABT 737
5.47	IC50	3390	nM	CHEMBL257619
5.45	IC50	3570	nM	TUBACIN
5.42	IC50	3810	nM	BLEOMYCIN
5.40	IC50	3950	nM	CHEMBL5414235
5.38	IC50	4120	nM	TUBACIN
5.38	IC50	4200	nM	CHEMBL5425377
5.36	IC50	4400	nM	VADADUSTAT
5.35	IC50	4470	nM	ABT 737
5.32	IC50	4770	nM	BELINOSTAT
5.31	IC50	4910	nM	TUBACIN
5.25	IC50	5690	nM	TUBACIN

PubChem BioAssay actives

56 with measured affinity, of 91 total; 31 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
pyridine-2,4-dicarboxylic acid	1677972: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis	ic50	0.0200	uM
5-fluoropyridine-2,4-dicarboxylic acid	2010695: Inhibition of AspH (unknown origin) by SPE-MS analysis	ic50	0.0500	uM
3-fluoropyridine-2,4-dicarboxylic acid	2010695: Inhibition of AspH (unknown origin) by SPE-MS analysis	ic50	0.1100	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149830: Binding affinity to human ASPH incubated for 45 mins by Kinobead based pull down assay	kd	0.2272	uM
7-(8-formyl-1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4-propan-2-ylnaphthalene-1-carbaldehyde	1677972: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis	ic50	0.2500	uM
3-(1-phenylethylamino)pyridine-2,4-dicarboxylic acid	2010694: Inhibition of N-terminal his6-tagged human recombinant AspH (315 to 758 residues) expressed in Escherichia coli BL21 (DE3) cells by SPE-MS analysis	ic50	0.2800	uM
5-(benzylamino)pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	0.5000	uM
3-[(4-methoxyphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010694: Inhibition of N-terminal his6-tagged human recombinant AspH (315 to 758 residues) expressed in Escherichia coli BL21 (DE3) cells by SPE-MS analysis	ic50	0.5800	uM
4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide	1677974: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and high 20 uM FAS incubated for 35 mins by MS analysis	ic50	0.8000	uM
5-[(2-methoxyphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	0.9000	uM
5-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	1.2000	uM
3-(1-phenylpropylamino)pyridine-2,4-dicarboxylic acid	2010694: Inhibition of N-terminal his6-tagged human recombinant AspH (315 to 758 residues) expressed in Escherichia coli BL21 (DE3) cells by SPE-MS analysis	ic50	1.2200	uM
Venetoclax	1677974: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and high 20 uM FAS incubated for 35 mins by MS analysis	ic50	1.2900	uM
3-[[2-[2-[2-[[(2S,3R)-2-[[(2S,3S,4R)-4-[[(2S,3R)-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2R,3S,4S,5S,6S)-3-[(2R,3S,4S,5R,6R)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxy-2-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]ethyl]-1,3-thiazol-4-yl]-1,3-thiazole-4-carbonyl]amino]propyl-dimethylsulfanium	1677972: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis	ic50	1.4700	uM
5-(2-phenylethylamino)pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	1.8000	uM
3-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-2,4-dicarboxylic acid	2010694: Inhibition of N-terminal his6-tagged human recombinant AspH (315 to 758 residues) expressed in Escherichia coli BL21 (DE3) cells by SPE-MS analysis	ic50	1.8600	uM
5-(4-phenylbutylamino)pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	1.9000	uM
5-[(4-methoxyphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	2.0000	uM
5-(cyclohexylmethylamino)pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	2.6000	uM
5-(3-phenylpropylamino)pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	2.8000	uM
4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide	1677974: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and high 20 uM FAS incubated for 35 mins by MS analysis	ic50	2.9200	uM
Belinostat	1677974: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and high 20 uM FAS incubated for 35 mins by MS analysis	ic50	3.1000	uM
(2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5S,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5R,6R)-4-[(2S,4R,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-8,9-dihydroxy-7-methyl-3,4-dihydro-2H-anthracen-1-one	1677975: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using high 10 uM hFX-CP as substrate mixture with 10 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis	ic50	3.3900	uM
N-[4-[(2R,4R,6S)-4-[(4,5-diphenyl-1,3-oxazol-2-yl)sulfanylmethyl]-6-[4-(hydroxymethyl)phenyl]-1,3-dioxan-2-yl]phenyl]-N’-hydroxyoctanediamide	1677975: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using high 10 uM hFX-CP as substrate mixture with 10 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis	ic50	3.5700	uM
3-(benzylamino)pyridine-2,4-dicarboxylic acid	2010694: Inhibition of N-terminal his6-tagged human recombinant AspH (315 to 758 residues) expressed in Escherichia coli BL21 (DE3) cells by SPE-MS analysis	ic50	3.9500	uM
5-(trifluoromethyl)pyridine-2,4-dicarboxylic acid	2010695: Inhibition of AspH (unknown origin) by SPE-MS analysis	ic50	4.2000	uM
5-(1-phenylethylamino)pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	5.9000	uM
Midostaurin	1677975: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using high 10 uM hFX-CP as substrate mixture with 10 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis	ic50	6.0200	uM
3-(2-phenylethylamino)pyridine-2,4-dicarboxylic acid	2010694: Inhibition of N-terminal his6-tagged human recombinant AspH (315 to 758 residues) expressed in Escherichia coli BL21 (DE3) cells by SPE-MS analysis	ic50	7.6600	uM
5-[(2-cyclopropylphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010697: Inhibition of N-terminal his6-tagged AspH (315 to 758 residues) (unknown origin) expressed in Escherichia coli by SPE-MS analysis	ic50	8.9000	uM
(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid	1677975: Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using high 10 uM hFX-CP as substrate mixture with 10 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis	ic50	9.4400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression, affects expression	5
bisphenol A	affects expression, affects cotreatment, affects methylation, decreases expression, decreases methylation (+1 more)	4
Benzo(a)pyrene	increases expression, increases methylation, increases mutagenesis	4
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	4
lead acetate	increases expression	2
sodium arsenite	affects expression, increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Doxorubicin	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	increases expression, affects cotreatment, decreases expression, affects expression	2
Tretinoin	decreases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	increases abundance, increases palmitoylation, increases expression, decreases reaction	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
sodium arsenate	decreases expression	1
terbufos	increases methylation	1
trichostatin A	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
cupric chloride	increases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4672386	Binding	Binding affinity to human AspH assessed as change in melting temperature	Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1LS	HyCyte A-549 KO-hASPH	Cancer cell line	Male
CVCL_SD65	HAP1 ASPH (-) 1	Cancer cell line	Male
CVCL_SD66	HAP1 ASPH (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03600376	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Ryanodex as Adjuvant Treatment in Subjects With EHS
NCT01624558	Not specified	WITHDRAWN	Effectiveness of Carbon Filters to Reduce the Anesthetic Gas Concentration in an Anesthetized Patient
NCT02561598	Not specified	WITHDRAWN	A Case Control Study of Patients With Diagnosis of Malignant Hyperthermia
NCT02964481	Not specified	TERMINATED	Malignant Hyperthermia Registry and Genetic Testing
NCT03964870	Not specified	UNKNOWN	Spanish Registry of RYR1 and CACNA1S Polymorphisms
NCT04474860	Not specified	UNKNOWN	Gene Mutation Spectrum of Malignant Hyperthermia in China
NCT04610619	Not specified	UNKNOWN	Multisystem Features of Malignant Hyperthermia or Rhabdomyolysis Related to RYR1 Variants
NCT05036148	Not specified	COMPLETED	Malignant Hyperthermia in Czech Republic: Description of the Biggest Slavonic Group of Patients Investigated for Risk of Malignant Hyperthermia
NCT05402839	Not specified	RECRUITING	Screening of Malignant Hyperthermia Susceptible Individuals
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT05764980	Not specified	UNKNOWN	Neurovisual Function in CHARGE Syndrome
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07320482	Not specified	COMPLETED	A Strategic Approach to Safe and Effective Cochlear Implantation in Patients With CHARGE Syndrome