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): 331 total — 19 pathogenic, 17 likely-pathogenic (top 10% of genes corpus-wide)
• GTEx eGene: eQTL in 23 tissues, sQTL in 40 (q < 0.05)
• Phenotypes (HPO): 37
• ChEMBL bioactivity: 13 clinical-phase molecules tested; no curated mechanism-of-action drug
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.01 (unconstrained)
• 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: 212 — 187 protein_coding, 16 nonsense_mediated_decay, 6 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000379454

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 8, TSL 2: 6, TSL 3: 7, TSL 4: 4, TSL 5: 5

ENST00000379454, ENST00000356457, ENST00000379449, 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, ENST00000994089, ENST00000994090, ENST00000994091, ENST00000994092, ENST00000994093, ENST00000994094, ENST00000994095, ENST00000994096, ENST00000994097, ENST00000994098, ENST00000994099, ENST00000994100, ENST00000994101, ENST00000994102, ENST00000994103, ENST00000994104, ENST00000994105, ENST00000994106, ENST00000994107, ENST00000994108, ENST00000994109, ENST00000994110, ENST00000994111, ENST00000994112, ENST00000994113, ENST00000994114, ENST00000994115, ENST00000994116, ENST00000994117, ENST00000994118, ENST00000994119, ENST00000994120, ENST00000994122, ENST00000994123, ENST00000994124, ENST00000994125, ENST00001030515, ENST00001030516, ENST00001030517, ENST00001030518, ENST00001030519, ENST00001030520, ENST00001030521, ENST00001030522, ENST00001030523, ENST00001030524, ENST00001030526, ENST00001030527, ENST00001030528, ENST00001030529, ENST00001030530, ENST00001030531, ENST00001030532, ENST00001030533, ENST00001030534, ENST00001030535, ENST00001030536, ENST00001030537, ENST00001030538, ENST00001030539, ENST00001030540, ENST00001030541, ENST00001030542, ENST00001030543, ENST00001030545, ENST00001030546, ENST00001030547, ENST00001030548, ENST00001030549, ENST00001030550, ENST00001030551, ENST00001030552, ENST00001030553, ENST00001030554, ENST00001030555, ENST00001030556, ENST00001030557, ENST00001030558, ENST00001030560, ENST00001030561, ENST00001082416, ENST00001082417, ENST00001104286, ENST00001106171, ENST00001106172, ENST00001106173, ENST00001106174, ENST00001114425, ENST00001114426, ENST00001114427, ENST00001114428, ENST00001127880, ENST00001127881, ENST00001127882, ENST00001127883, ENST00001127884, ENST00001127885, ENST00001127886, ENST00001127887, ENST00001127888, ENST00001127889, ENST00001134283

RefSeq mRNA: 78 — 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_001439196, 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.

Highest expression (Bgee): calcaneal tendon, stromal cell of endometrium, palpebral conjunctiva, colonic epithelium, adrenal tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ASPH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 40 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 63 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	4.7e-66	-0.98	8:61682509:C:T
Muscle Skeletal	sqtl	1.9e-59	+0.89	8:61627218:T:C
Adipose Subcutaneous	sqtl	1.6e-32	-0.85	8:61648023:A:G
Heart Atrial Appendage	sqtl	1.2e-24	-0.97	8:61686215:G:A
Adipose Visceral Omentum	sqtl	2.7e-20	-0.84	8:61645295:A:G
Nerve Tibial	sqtl	4.0e-19	-0.67	8:61631869:G:T
Artery Tibial	sqtl	8.0e-19	+0.56	8:61515250:A:C
Heart Left Ventricle	sqtl	2.7e-14	-0.86	8:61682509:C:T
Breast Mammary Tissue	sqtl	2.9e-13	-0.71	8:61678164:C:G
Thyroid	sqtl	2.1e-12	+0.54	8:61662228:T:C
Whole Blood	eqtl	4.2e-12	+0.18	8:61731224:C:T
Skin Sun Exposed Lower leg	sqtl	8.1e-12	+0.42	8:61630949:G:A
Brain Anterior cingulate cortex BA24	sqtl	1.8e-10	-0.56	8:61620418:GTTGA:G
Esophagus Muscularis	sqtl	3.2e-10	+0.52	8:61615855:A:T
Esophagus Mucosa	sqtl	7.0e-10	+0.27	8:61674486:G:A
Brain Nucleus accumbens basal ganglia	sqtl	7.3e-10	-0.57	8:61641296:T:C
Colon Transverse	sqtl	1.1e-09	+0.58	8:61669619:C:T
Brain Caudate basal ganglia	sqtl	1.3e-09	-0.58	8:61648225:C:T
Colon Sigmoid	sqtl	3.7e-09	-0.65	8:61629436:G:T
Brain Cerebellar Hemisphere	sqtl	3.9e-09	-0.43	8:61620418:GTTGA:G

FANTOM5 promoters

showing 10 of 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

showing 100 of 295 tissues 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
rectum	UBERON:0001052	97.58	gold quality
epithelium of mammary gland	UBERON:0003244	97.32	gold quality
parietal pleura	UBERON:0002400	97.29	gold quality
mammary duct	UBERON:0001765	97.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.21	gold quality
mucosa of stomach	UBERON:0001199	97.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.19	gold quality
pleura	UBERON:0000977	96.95	gold quality
gall bladder	UBERON:0002110	96.94	gold quality
medial globus pallidus	UBERON:0002477	96.94	gold quality
descending thoracic aorta	UBERON:0002345	96.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.86	gold quality
visceral pleura	UBERON:0002401	96.82	gold quality
tendon of biceps brachii	UBERON:0008188	96.81	gold quality
popliteal artery	UBERON:0002250	96.77	gold quality
tibial artery	UBERON:0007610	96.77	gold quality
minor salivary gland	UBERON:0001830	96.75	gold quality
smooth muscle tissue	UBERON:0001135	96.72	gold quality
urinary bladder	UBERON:0001255	96.71	gold quality
stomach	UBERON:0000945	96.67	gold quality
tibial nerve	UBERON:0001323	96.64	gold quality
right atrium auricular region	UBERON:0006631	96.59	gold quality
body of stomach	UBERON:0001161	96.56	gold quality
aorta	UBERON:0000947	96.53	gold quality
esophagus squamous epithelium	UBERON:0006920	96.39	gold quality
cerebellar hemisphere	UBERON:0002245	96.38	gold quality
left coronary artery	UBERON:0001626	96.37	gold quality
endothelial cell	CL:0000115	96.36	silver quality
thoracic aorta	UBERON:0001515	96.26	gold quality
mouth mucosa	UBERON:0003729	96.25	gold quality
epithelial cell of pancreas	CL:0000083	96.24	gold quality
cerebellar cortex	UBERON:0002129	96.22	gold quality
ascending aorta	UBERON:0001496	96.21	gold quality
left lobe of thyroid gland	UBERON:0001120	96.14	gold quality
epithelium of nasopharynx	UBERON:0001951	96.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.12	gold quality
left uterine tube	UBERON:0001303	96.11	gold quality
coronary artery	UBERON:0001621	96.11	gold quality
blood vessel layer	UBERON:0004797	96.07	gold quality
thyroid gland	UBERON:0002046	95.98	gold quality
gingival epithelium	UBERON:0001949	95.97	gold quality
saliva-secreting gland	UBERON:0001044	95.95	gold quality
globus pallidus	UBERON:0001875	95.88	gold quality
amniotic fluid	UBERON:0000173	95.82	gold quality
right lobe of thyroid gland	UBERON:0001119	95.81	gold quality
nucleus accumbens	UBERON:0001882	95.79	gold quality
putamen	UBERON:0001874	95.75	gold quality
cardiac atrium	UBERON:0002081	95.69	gold quality
right lung	UBERON:0002167	95.63	gold quality
nasal cavity mucosa	UBERON:0001826	95.60	gold quality
fundus of stomach	UBERON:0001160	95.45	gold quality
amygdala	UBERON:0001876	95.38	gold quality
right frontal lobe	UBERON:0002810	95.38	gold quality
squamous epithelium	UBERON:0006914	95.35	gold quality
right coronary artery	UBERON:0001625	95.33	gold quality
pancreas	UBERON:0001264	95.30	gold quality
upper arm skin	UBERON:0004263	95.27	gold quality
caudate nucleus	UBERON:0001873	95.21	gold quality
heart	UBERON:0000948	95.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.16	gold quality
right ovary	UBERON:0002118	95.12	gold quality
ovary	UBERON:0000992	95.10	gold quality
gingiva	UBERON:0001828	95.10	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.06	gold quality
heart left ventricle	UBERON:0002084	95.04	gold quality
urethra	UBERON:0000057	95.03	gold quality
pigmented layer of retina	UBERON:0001782	95.02	gold quality
tonsil	UBERON:0002372	95.02	gold quality
epithelium of esophagus	UBERON:0001976	94.95	gold quality
muscle organ	UBERON:0001630	94.94	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Adipose tissue	tissue	362.0	high
Skeletal muscle	tissue	331.0	not detected
Retina	tissue	201.9
Postcentral gyrus	tissue	192.3
Choroid plexus	tissue	187.3
Tongue	tissue	155.4
Adrenal gland	tissue	150.8	high
Hippocampus	tissue	143.8	high
Nucleus accumbens	tissue	137.8
Locus coeruleus	tissue	106.9
Urinary bladder	tissue	103.6	high
Heart muscle	tissue	100.1	not detected
Breast	tissue	99.5	high
Stomach 1	tissue	96.9	medium
Frontal cortex	tissue	96.6
Salivary gland	tissue	95.6	high
Thyroid gland	tissue	90.3	medium
Rectum	tissue	77.9	high
Colon	tissue	72.8	high
Liver	tissue	69.9	not detected
Lung	tissue	69.4	medium
Esophagus	tissue	66.3	medium
Seminal vesicle	tissue	65.8	medium
Smooth muscle	tissue	62.4	low
Cervix	tissue	60.9	medium
Olfactory bulb	tissue	60.0
Ovary	tissue	58.7	medium
Cerebellum	tissue	58.5	high
Caudate putamen	tissue	57.6
Gallbladder	tissue	56.5	medium
Kidney	tissue	55.2	medium
Spinal cord	tissue	49.6
Appendix	tissue	47.6	medium
Endometrium 1	tissue	45.6	medium
Placenta	tissue	44.6	medium
Prostate	tissue	44.4	low
Duodenum	tissue	42.9	medium
Small intestine	tissue	42.6	medium
Epididymis	tissue	42.3	medium
Pancreas	tissue	42.1	high
Vagina	tissue	40.4	low
Hypothalamus	tissue	39.4
Amygdala	tissue	38.3
Pons	tissue	37.7
Thalamus	tissue	37.3
Substantia nigra	tissue	36.4
Superior colliculi	tissue	36.0
Periaqueductal gray	tissue	35.9
Midbrain	tissue	35.8
Hippocampal formation	tissue	35.8
Parathyroid gland	tissue	35.7	not detected
Septum	tissue	35.3
Prefrontal cortex	tissue	34.6
Cerebral cortex	tissue	34.6	high
Medulla oblongata	tissue	34.5
Somatosensory cortex	tissue	34.0
Pituitary gland	tissue	33.8
Temporal cortex	tissue	33.8
Retrosplenial and cingulate cortex	tissue	33.2
Entorhinal cortex	tissue	32.8

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Cerebellar cortex (218.8), Vermis (204.9), Flocculonodular lobe (204.8), Inferior parietal lobule (162.2), Habenula (159.6).

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

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

showing 30 of 157 miRNAs:

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

gnomAD constraint: pLI 2.74e-21, LOEUF 1.01, missense Z -0.0873 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000379454 — one region, missense o/e 1.00. 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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1914186) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
cleft palate	1
short snout	1
syndactyly	1
irregular heartbeat	1
reduced female fertility	1
decreased litter size	1
premature death	1
abnormal myocardial fiber physiology	1
abnormal response of heart to induced stress	1
increased cardiac muscle contractility	1
abnormal sinoatrial node conduction	1
ventricular tachycardia	1
ventricular premature beat	1
atrioventricular block	1

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
Bos taurus	A1L515	88.8%	Diamond
Xenopus tropicalis	B5DE73	81.1%	Diamond
Martinezella tropici	Q4VFY5	39.4%	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
LINC02842	ncRNA	101929628
LINC02155	ncRNA	111082988
MIR4470	ncRNA	100616484
CLVS1	protein-coding	157807

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, G3XAN5, Q12797

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 (78): 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_001426125, 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)

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

UniProt features (88 total): helix 22, 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)

showing 30 of 43 structures by resolution:

PDB	Title	Method	Resolution (Å)
6YYX	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.53
7YB9	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.54
9FVV	Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex with Mn, 2OG, thiocyanate and …	X-RAY DIFFRACTION	1.6
6Q9F	Aspartyl/Asparaginyl beta-hydroxylase (AspH) H679A in complex with Mn, NOG and Factor X …	X-RAY DIFFRACTION	1.63
7BMI	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.66
7YBB	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.68
8RE5	Aspartyl/Asparaginyl beta-hydroxylase (AspH) R735Q variant in complex with Mn …	X-RAY DIFFRACTION	1.7
9FVU	Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex with Fe, 2-oxoglutarate …	X-RAY DIFFRACTION	1.7
7BMJ	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.75
6YYV	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.77
6Z6Q	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.81
9HO2	Room temperature structure of Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex …	X-RAY DIFFRACTION	1.83
7YBC	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.84
8RE9	Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex with Mn, 2-oxoglutarate and a …	X-RAY DIFFRACTION	1.84
8RE8	Aspartyl/Asparaginyl beta-hydroxylase (AspH) R688Q variant in complex with Mn …	X-RAY DIFFRACTION	1.85
9HO1	Room temperature structure of Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex …	X-RAY DIFFRACTION	1.85
6Q9I	Aspartyl/Asparaginyl beta-hydroxylase (AspH) H679A in complex with Factor X peptide …	X-RAY DIFFRACTION	1.85
7YBA	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.86
7E6J	Aspartyl/Asparaginyl beta-hydroxylase (AspH) H725A in complex with Factor X peptide …	X-RAY DIFFRACTION	1.9
9FVW	Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex with Fe, 2OG, SIN and …	X-RAY DIFFRACTION	1.9
9FVX	Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex with Fe, 2-oxoglutarate and …	X-RAY DIFFRACTION	1.9
9FVY	Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex with Fe, 2-oxoglutarate …	X-RAY DIFFRACTION	1.9
8RE6	Aspartyl/Asparaginyl beta-hydroxylase (AspH) R735Q variant in complex with Mn …	X-RAY DIFFRACTION	1.92
8RE7	Aspartyl/Asparaginyl beta-hydroxylase (AspH) R735W variant in complex with Mn …	X-RAY DIFFRACTION	1.95
9FW0	Room temperature structure of Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex …	X-RAY DIFFRACTION	1.95
7YB8	Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.98
9FVZ	Aspartyl/Asparaginyl beta-hydroxylase (AspH) in complex with Fe, 2-oxoglutarate and a …	X-RAY DIFFRACTION	1.98
5JQY	Aspartyl/Asparaginyl beta-hydroxylase (AspH)oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	1.99
5APA	Crystal structure of human aspartate beta-hydroxylase isoform a	X-RAY DIFFRACTION	2.05
5JZ8	Aspartyl/Asparaginyl beta-hydroxylase (AspH)oxygenase and TPR domains in complex with …	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum

Antibody reliability (HPA): IH uncertain · IF enhanced

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)

Position	Role
91	Ca(2+)
93	Ca(2+)
95	Ca(2+)
97	Ca(2+)
102	Ca(2+)
625	2-oxoglutarate
668	2-oxoglutarate
679	Fe cation
688–690	2-oxoglutarate
725	Fe cation
735	2-oxoglutarate

Post-translational modifications (1)

Type	Positions
Phosphoserine	14

Disulfide bonds (1)

Type	Positions
Disulfide bond	641–648

Glycosylation sites (3)

Type	Positions
N-linked (glcnac…) asparagine	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

2 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

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

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 (19): detection of calcium ion (GO:0005513), muscle contraction (GO:0006936), 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), regulation of protein stability (GO:0031647), activation of store-operated calcium channel activity (GO:0032237), response to ATP (GO:0033198), positive regulation of proteolysis (GO:0045862), positive regulation of DNA-templated transcription (GO:0045893), phosphatidylinositol-mediated signaling (GO:0048015), regulation of cytosolic calcium ion concentration (GO:0051480), calcium ion homeostasis (GO:0055074), 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-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 (10): 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)

Reactome top-level categories

7 top-level categories:

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

showing 60 of 66 GO namespaces:

Category	Terms
response to calcium ion	2
molecular_function	2
sarcoplasmic reticulum	2
cellular anatomical structure	2
detection of chemical stimulus	1
muscle system 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
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 signal transduction	1
intracellular calcium ion homeostasis	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
cellular response to metal ion	1
intracellular protein transport	1
positive regulation of intracellular transport	1
regulation of intracellular protein transport	1
positive regulation of protein transport	1
regulation of protein-containing complex disassembly	1
protein depolymerization	1
protein hydroxylation	1
metal ion binding	1
structural molecule activity	1
protein binding	1
2-oxoglutarate-dependent dioxygenase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
cation binding	1
oxidoreductase activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
sarcoplasmic reticulum membrane	1
cell cortex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 40 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
activation of store-operated calcium channel activity	BP	direct assay
calcium ion homeostasis	BP	direct assay
calcium ion transmembrane transport	BP	direct assay
cellular response to calcium ion	BP	direct assay
phosphatidylinositol-mediated signaling	BP	direct assay
positive regulation of DNA-templated transcription	BP	mutant phenotype
positive regulation of calcium ion transport into cytosol	BP	direct assay
positive regulation of intracellular protein transport	BP	direct assay
positive regulation of proteolysis	BP	direct assay
response to ATP	BP	direct assay
cortical endoplasmic reticulum	CC	direct assay
endoplasmic reticulum	CC	direct assay
endoplasmic reticulum membrane	CC	direct assay
plasma membrane	CC	direct assay
calcium ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,170 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASPH	TRDN	Q13061	981
ASPH	RYR2	Q92736	927
ASPH	CASQ2	O14958	874
ASPH	CASQ1	P31415	849
ASPH	FKBP1B	P68106	837
ASPH	RYR1	P21817	826
ASPH	MTA3	Q9BTC8	782
ASPH	SRRT	Q9BXP5	664
ASPH	C1R	P00736	566
ASPH	C1S	P09871	551
ASPH	JPH4	Q96JJ6	550
ASPH	JPH1	Q9HDC5	547
ASPH	MTA1	Q13330	545
ASPH	JPH2	Q9BR39	535
ASPH	CALR	P27797	530

IntAct

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

7 partners by confidence:

Partner	Interaction type	MIscore	Records
STXBP3	association	0.640	3
GET3	physical association	0.560	3
HTT	physical association	0.400	1
ECE1	physical association	0.370	2
CHRM5	physical association	0.370	1
PDGFRL	physical association	0.370	1
POTEF	association	0.350	1

BioGRID (443 interactions; top human partners by supporting records): FBLN7 (Affinity Capture-MS; 3 records), HLA-E (Affinity Capture-MS; 3 records), LRRC59 (Affinity Capture-MS; 3 records), OLFM1 (Affinity Capture-MS; 3 records), PTCH1 (Affinity Capture-MS; 3 records), PVRL3 (Affinity Capture-MS; 3 records), VTI1B (Affinity Capture-MS; 3 records), ACAD9 (Affinity Capture-MS; 2 records), ANLN (Affinity Capture-MS; 2 records), ASNA1 (Two-hybrid; 2 records), ATP2C2 (Proximity Label-MS; 2 records), BCHE (Affinity Capture-MS; 2 records), BNIP1 (Affinity Capture-MS; 2 records), CANX (Co-fractionation; 2 records), CCDC109B (Affinity Capture-MS; 2 records)

Disease & clinical

Genetic variants

Variant evidence for ASPH: 331 ClinVar records (36 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	17
Uncertain significance	108
Likely benign	68
Benign	60

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 36 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
137615	NM_004318.4(ASPH):c.2203C>T (p.Arg735Trp)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
1210220	NM_004318.4(ASPH):c.1782G>A (p.Trp594Ter)	Pathogenic	criteria provided, single submitter	1
1426171	NM_004318.4(ASPH):c.1916dup (p.Asn639fs)	Pathogenic	criteria provided, single submitter	1
1915255	NM_004318.4(ASPH):c.1892G>A (p.Trp631Ter)	Pathogenic	criteria provided, single submitter	1
2429371	NM_004318.4(ASPH):c.1394del (p.Leu465fs)	Pathogenic	criteria provided, single submitter	1
2768808	NM_004318.4(ASPH):c.1482T>A (p.Tyr494Ter)	Pathogenic	criteria provided, single submitter	1
3776052	NM_004318.4(ASPH):c.1552G>T (p.Gly518Ter)	Pathogenic	criteria provided, single submitter	1
3900997	NM_004318.4(ASPH):c.1724G>A (p.Trp575Ter)	Pathogenic	criteria provided, single submitter	1
4531227	NM_004318.4(ASPH):c.1910del (p.Asn637fs)	Pathogenic	criteria provided, single submitter	1
4347901	NM_004318.4(ASPH):c.2204G>A (p.Arg735Gln)	Likely pathogenic	criteria provided, single submitter	2
1210559	NM_004318.4(ASPH):c.1771G>T (p.Glu591Ter)	Likely pathogenic	criteria provided, single submitter	1
1691259	NM_004318.4(ASPH):c.1626G>A (p.Glu542=)	Likely pathogenic	criteria provided, single submitter	1
2860956	NM_004318.4(ASPH):c.1149+1G>A	Likely pathogenic	criteria provided, single submitter	1
3065095	NM_004318.4(ASPH):c.1680G>A (p.Trp560Ter)	Likely pathogenic	criteria provided, single submitter	1
3383478	NM_004318.4(ASPH):c.2160del (p.Asp720fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ASPH’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.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 3,274):

Position(s)	Effect	Δscore	Sites
8:61555922–61555923	donor_loss	1.0000	5
8:61556023	acceptor_loss	1.0000
8:61562897	acceptor_gain	1.0000
8:61619020–61619021	acceptor_loss	1.0000	6
8:61626159	donor_gain	1.0000
8:61643378	donor_gain	1.0000
8:61644598–61644599	donor_loss	1.0000	5
8:61644633–61644634	acceptor_loss	1.0000	5
8:61646752	donor_gain	1.0000
8:61653723	acceptor_gain	1.0000

AlphaMissense

1,756 missense substitutions predicted likely pathogenic (of 5,019 scored), across 401 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
M670	9	0.876	0.998
D721	8	0.999	1.000
H679	8	0.998	1.000
H725	8	0.998	0.999
D741	8	0.998	1.000
D720	8	0.997	1.000
H690	8	0.994	0.999
D102	8	0.993	0.996
H744	8	0.990	0.998
F556	8	0.986	0.999
D533	8	0.983	0.998
D91	8	0.981	0.992
F719	8	0.980	0.998
D99	8	0.978	0.992
D95	8	0.976	0.994
F496	8	0.976	0.999
H493	8	0.974	0.999
F432	8	0.973	0.999
F98	8	0.972	0.997
N684	8	0.970	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

4 prognostic cancer types:

Cancer	Prognostic	p-value
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	9.4e-07
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	5.81e-06
Lung Adenocarcinoma (TCGA)	unfavorable	3.07e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	4.57e-05

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome	Strong	Autosomal recessive	4
malignant hyperthermia of anesthesia	Moderate	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
DDG2P	green
Paediatric disorders	green
Structural eye disease	green
Thoracic aortic aneurysm or dissection (GMS)	green

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

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

HPO phenotypes

37 phenotypes (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
HP:0011003	High myopia
HP:0011463	Childhood onset
HP:0011483	Anterior synechiae of the anterior chamber
HP:0012629	Phakodonesis
HP:0020125	Spontaneous conjunctival filtering bleb
HP:0031624	Moderate myopia
HP:0034375	Spherophakia

GWAS associations

5 associations:

Study	Trait	p-value
GCST006585_2271	Blood protein levels	4e-18
GCST004213_4	Resting heart rate	2e-8
GCST006719_5	BRCA1/2-negative high-risk breast cancer	8e-7
GCST002829_30	Urate levels in overweight individuals	4e-6
GCST010314_2	Serum omega-6 to omega-3 polyunsaturated fatty acid ratio in metabolic syndrome	7e-6

EFO canonical traits (from GWAS)

3 canonical traits:

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 disease descriptors:

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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 68,201 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

13 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL408513	BELINOSTAT	4	8,184
CHEMBL6067492	BLEOMYCIN	4
CHEMBL3544988	DAPRODUSTAT	4	326
CHEMBL608533	MIDOSTAURIN	4	7,641
CHEMBL2338329	ROXADUSTAT	4	1,097
CHEMBL3646221	VADADUSTAT	4	559
CHEMBL1229517	VEMURAFENIB	4	16,487
CHEMBL3137309	VENETOCLAX	4	9,905
CHEMBL4650314	DESIDUSTAT	3	273
CHEMBL4297619	ENARODUSTAT	3	121
CHEMBL51483	GOSSYPOL	3	14,167
CHEMBL443684	NAVITOCLAX	3	5,008
CHEMBL376408	ABT 737	1	4,433

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	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

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs4379440	warfarin	Efficacy	Allele T is associated with decreased time in therapeutic range when treated with warfarin as compared to allele G.	PMID:27488176

Binding affinities (BindingDB)

48 measured of 53 human assays (54 total across all organisms); most potent 48 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
ABT-199	IC50	1.2 nM	US-11420968: Bcl-2 inhibitors
ABT-263	IC50	10 nM
PLX-4032	IC50	19 nM
CHEMBL5422782	IC50	50 nM
PKC-412	KD	110 nM
CHEMBL5430087	IC50	110 nM
CHEMBL5429223	IC50	280 nM
CHEMBL5425339	IC50	500 nM
CHEMBL5415306	IC50	580 nM
CHEMBL5428941	IC50	900 nM
Vadadustat	IC50	1100 nM	US-11426393: Prolyl hydroxylase inhibitors and methods of use
Tash 1	IC50	1200 nM
CHEMBL5407378	IC50	1200 nM
CHEMBL5429166	IC50	1220 nM
CHEBI:3139	IC50	1470 nM
CHEMBL5434665	IC50	1800 nM
CHEMBL5423241	IC50	1860 nM
CHEMBL5419332	IC50	1900 nM
CHEMBL5396670	IC50	2000 nM
CHEMBL6148285	IC50	2300 nM
CHEMBL6173707	IC50	2500 nM
CHEMBL5423565	IC50	2600 nM
CHEMBL5402035	IC50	2800 nM
CHEMBL5414235	IC50	3950 nM
CHEMBL5425377	IC50	4200 nM
CHEMBL5408048	IC50	5900 nM
N-(4-{(2R,4R,6S)-4-{[(4,5-diphenyl-1,3-oxazol-2-yl)sulfanyl]methyl}-6-[4-(hydroxymethyl)phenyl]-1,3-dioxan-2-yl}phenyl)-N -hydroxyoctanediamide	IC50	6270 nM
CHEMBL5401915	IC50	7660 nM
CHEMBL6148803	IC50	8200 nM
CHEMBL5408058	IC50	8900 nM
CHEMBL4166742	IC50	9600 nM
CHEMBL6162468	IC50	9700 nM
2-[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid	IC50	9800 nM	US-9115085: Crystalline forms of a prolyl hydroxylase inhibitor
Desidustat	IC50	9900 nM
4-(4-{[2-(4-chlorophenyl)phenyl]methyl}piperazin-1-yl)-N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene)sulfonyl]benzamide	IC50	10000 nM
CHEMBL5438950	IC50	10800 nM
CHEMBL5414033	IC50	10900 nM
CHEMBL6133035	IC50	11000 nM
DAPRODUSTAT	IC50	11100 nM
Belinostat	IC50	11200 nM
CHEMBL4777255	IC50	11900 nM
CHEBI:31856	IC50	12200 nM
CHEMBL5397863	IC50	13100 nM
CHEMBL5409822	IC50	16100 nM
CHEMBL6166855	IC50	17000 nM
CHEMBL6161729	IC50	17000 nM
CHEMBL6161843	IC50	18000 nM
pyridine-2,4-dicarboxylic acid	IC50	347000 nM

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

59 with measured affinity, of 104 total; 37 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
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
1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-N-(2H-tetrazol-5-ylmethyl)quinoline-3-carboxamide	2246821: Inhibition of N-terminal His6-tagged recombinant human AspH (315 to 758 residues) extracted from Escherichia coli BL21 (DE3) cells using hFX-CP/2-OG as substrate by SPE-MS analysis	ic50	2.3000	uM
2-[[4-hydroxy-1-(naphthalen-1-ylmethoxy)-2-oxoquinoline-3-carbonyl]amino]acetic acid	2246821: Inhibition of N-terminal His6-tagged recombinant human AspH (315 to 758 residues) extracted from Escherichia coli BL21 (DE3) cells using hFX-CP/2-OG as substrate by SPE-MS analysis	ic50	2.5000	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
Vadadustat	2246826: Inhibition of AspH (unknown origin)	ic50	4.4000	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
2-[[1-(cyclopropylmethoxy)-4-hydroxy-2-oxoquinoline-3-carbonyl]amino]propanoic acid	2246821: Inhibition of N-terminal His6-tagged recombinant human AspH (315 to 758 residues) extracted from Escherichia coli BL21 (DE3) cells using hFX-CP/2-OG as substrate by SPE-MS analysis	ic50	8.2000	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
2-[[7-oxo-5-(2-phenylethyl)-3H-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino]acetic acid	2246826: Inhibition of AspH (unknown origin)	ic50	9.6000	uM
2-[[4-hydroxy-2-oxo-1-(1,3-thiazol-4-ylmethoxy)quinoline-3-carbonyl]amino]-2-methylpropanoic acid	2246821: Inhibition of N-terminal His6-tagged recombinant human AspH (315 to 758 residues) extracted from Escherichia coli BL21 (DE3) cells using hFX-CP/2-OG as substrate by SPE-MS analysis	ic50	9.7000	uM
2-[[1-(cyclopropylmethoxy)-4-hydroxy-2-oxoquinoline-3-carbonyl]amino]acetic acid	2246826: Inhibition of AspH (unknown origin)	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	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	increases expression, affects expression, affects cotreatment, decreases 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	decreases reaction, increases abundance, increases palmitoylation, increases expression	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)

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

14 trials:

NCT	Phase	Status	Title
NCT03600376	Phase 3	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

Predicted chemistry — Sugi Predict

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