ITIH4

Summary

ITIH4 (inter-alpha-trypsin inhibitor heavy chain 4, HGNC:6169) is a protein-coding gene on chromosome 3p21.1, encoding Inter-alpha-trypsin inhibitor heavy chain H4 (Q14624). Type II acute-phase protein (APP) involved in inflammatory responses to trauma.

The protein encoded by this gene is secreted into the blood, where it is cleaved by plasma kallikrein into two smaller forms. Expression of this gene has been detected only in liver, and it seems to be upregulated during surgical trauma. This gene is part of a cluster of similar genes on chromosome 3. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3700 — RefSeq curated summary.

At a glance

• GWAS associations: 33
• Clinical variants (ClinVar): 178 total
• MANE Select transcript: NM_002218

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6169
Approved symbol	ITIH4
Name	inter-alpha-trypsin inhibitor heavy chain 4
Location	3p21.1
Locus type	gene with protein product
Status	Approved
Aliases	IHRP, H4P
Ensembl gene	ENSG00000055955
Ensembl biotype	protein_coding
OMIM	600564
Entrez	3700

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 66 protein_coding, 7 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000266041, ENST00000406595, ENST00000441637, ENST00000461966, ENST00000464000, ENST00000467462, ENST00000471505, ENST00000481977, ENST00000483372, ENST00000484632, ENST00000485816, ENST00000485894, ENST00000491663, ENST00000537897, ENST00000855362, ENST00000855363, ENST00000855364, ENST00000855365, ENST00000855366, ENST00000855367, ENST00000855368, ENST00000855369, ENST00000855370, ENST00000855371, ENST00000855372, ENST00000855373, ENST00000855374, ENST00000855375, ENST00000855376, ENST00000855377, ENST00000855378, ENST00000855379, ENST00000855380, ENST00000855381, ENST00000855382, ENST00000855383, ENST00000855384, ENST00000855385, ENST00000855386, ENST00000855387, ENST00000855388, ENST00000855389, ENST00000855390, ENST00000855391, ENST00000855392, ENST00000855393, ENST00000855394, ENST00000855395, ENST00000855396, ENST00000855397, ENST00000855398, ENST00000855399, ENST00000855400, ENST00000855401, ENST00000855402, ENST00000855403, ENST00000855404, ENST00000855405, ENST00000855406, ENST00000855407, ENST00000855408, ENST00000855409, ENST00000855410, ENST00000855411, ENST00000855412, ENST00000953100, ENST00000953101, ENST00000953102, ENST00000953103, ENST00000953104, ENST00000953105, ENST00000953106, ENST00000953107, ENST00000953108, ENST00000953109, ENST00000953110

RefSeq mRNA: 2 — MANE Select: NM_002218 NM_001166449, NM_002218

CCDS: CCDS2865, CCDS54596

Canonical transcript exons

ENST00000266041 — 24 exons

Exon	Start	End
ENSE00000771627	52819754	52819792
ENSE00000771646	52819940	52819990
ENSE00001556455	52830553	52830672
ENSE00001859916	52812962	52813490
ENSE00003475193	52826541	52826651
ENSE00003475787	52820991	52821130
ENSE00003482020	52814209	52814363
ENSE00003490650	52816884	52817058
ENSE00003510347	52820291	52820317
ENSE00003518435	52818462	52818536
ENSE00003526671	52820631	52820785
ENSE00003551756	52818257	52818283
ENSE00003553540	52823556	52823741
ENSE00003569250	52824190	52824315
ENSE00003584779	52818052	52818168
ENSE00003600095	52824842	52824958
ENSE00003603431	52824397	52824565
ENSE00003607545	52829119	52829279
ENSE00003608657	52827093	52827197
ENSE00003654902	52813975	52814071
ENSE00003657227	52823823	52824004
ENSE00003668153	52826791	52826953
ENSE00003673528	52825886	52826014
ENSE00003682585	52819393	52819518

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 99.88.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 10.3698 / max 5201.9615, expressed in 52 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42482	10.1406	49
42479	0.1159	8
42476	0.0284	8
42477	0.0210	7
42478	0.0199	6
42473	0.0182	6
42480	0.0145	6
42472	0.0112	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.88	gold quality
right coronary artery	UBERON:0001625	97.94	gold quality
liver	UBERON:0002107	96.95	gold quality
popliteal artery	UBERON:0002250	96.66	gold quality
tibial artery	UBERON:0007610	96.65	gold quality
left coronary artery	UBERON:0001626	96.21	gold quality
body of pancreas	UBERON:0001150	95.22	gold quality
coronary artery	UBERON:0001621	94.74	gold quality
aorta	UBERON:0000947	94.14	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.60	gold quality
sperm	CL:0000019	92.68	gold quality
right adrenal gland cortex	UBERON:0035827	92.49	gold quality
right adrenal gland	UBERON:0001233	92.47	gold quality
gastrocnemius	UBERON:0001388	92.29	gold quality
descending thoracic aorta	UBERON:0002345	92.28	gold quality
left adrenal gland cortex	UBERON:0035825	91.84	gold quality
left adrenal gland	UBERON:0001234	91.80	gold quality
muscle of leg	UBERON:0001383	91.76	gold quality
thoracic aorta	UBERON:0001515	91.18	gold quality
ascending aorta	UBERON:0001496	90.89	gold quality
sural nerve	UBERON:0015488	88.96	gold quality
granulocyte	CL:0000094	88.89	gold quality
adrenal cortex	UBERON:0001235	88.39	gold quality
pancreas	UBERON:0001264	87.39	gold quality
adrenal gland	UBERON:0002369	87.29	gold quality
right testis	UBERON:0004534	87.06	gold quality
mucosa of stomach	UBERON:0001199	86.81	gold quality
skeletal muscle organ	UBERON:0014892	86.73	gold quality
left testis	UBERON:0004533	86.43	gold quality
spleen	UBERON:0002106	86.22	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	518.55
E-MTAB-5061	yes	124.40
E-HCAD-9	yes	58.38
E-ANND-3	no	3.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting ITIH4, 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-8068	99.98	73.85	2376
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4701-5P	96.45	68.41	1121
HSA-MIR-588	96.45	68.36	1127
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-381-5P	91.91	65.03	65

Literature-anchored findings (GeneRIF, showing 29)

• Genetic variation at ITIH4 locus is one of the likely candidate determinants for plasma cholesterol metabolisms (PMID:14661079)
• ITIH4 and MTJ1 co-immunoprecipitate from total liver protein extracts and SANT domain of HTJ1 protects the ITIH4(588-930) recombinant fragment (PMID:16271702)
• The inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) protein was significantly present more in interstial cystitis than controls (PMID:18455532)
• ITIH4 is an anti-inflammatory protein, and suggests that further investigation into its potential use in the diagnosis and prognosis of acute ischemic stroke is warranted. (PMID:19263524)
• Findings suggest that ITI-H4 expression may be used as a biomarker, which could facilitate the development of novel diagnostic and therapeutic tools. (PMID:21331437)
• A truncated fragment of inter-alpha-trypsin inhibitor heavy chain 4 was the sole protein found to be significantly enhanced in the prostate cancer patients compared to the controls. (PMID:23417432)
• Expression of the 85 kDa ITIH4 was substantial in amyotrophic lateral sclerosis compared with controls or patients with muscular dystrophy, Alzheimer diseases, or Parkinson diseases (PMID:23436019)
• A novel association between suicide attempt and the ITIH3/4-region in a combined group of patients with bipolar disorder, schizophrenia and related psychosis spectrum disorders. (PMID:24461634)
• Worse survival among HCC patients with low ITIH4. (PMID:24836184)
• Four novel body mass index-associated loci near the KCNQ1(rs2237892), ALDH2/MYL2 (rs671, rs12229654), ITIH4 (rs2535633) and NT5C2 (rs11191580) genes are identified in East Asian-ancestry populations. (PMID:24861553)
• Isoform-specific ITIH4 glycosylation and utilization of O-glycosylation sites on ITIH4 differs between cell lines and serum. (PMID:24884609)
• Serum ITIH4 may be a PM10-specific biomarker in COPD and may be related to inflammation. (PMID:25977605)
• confirmed the association of schizophrenia with ITIH3/4 in a Han Chinese population (PMID:26206863)
• ITIH4 peptide isoform as a preterm birth biomarker and its associated SNP implications (PMID:26408095)
• this report has further supported for associations of genetic variants in the ITIH4 and CALN1 genes with schizophrenia and provided the first evidence that the variants regulate ITIH4 AND CALN1 expression in the dorsolateral prefrontal cortex (PMID:26991396)
• Low ITIH4 expression is associated with Hepatocellular Carcinoma. (PMID:28828637)
• ITIH4 SNPs rs3821831 and rs2239547 were studied in pregnant depressed Japanese women. Compared with the TT genotype of ITIH4 SNP rs2239547, the CC genotype was significantly related to a reduced risk of depressive symptoms during pregnancy. SNP rs3821831 was not related to these symptoms.The GCCT haplotype of rs2535629, rs736408, rs3821831, and rs2239547 was significantly positively associated with depressive symptoms. (PMID:29992445)
• The ITI-H4 (N(688)) might be a crucial inflammatory factor which contributes to the pathogenesis of recurrent pregnancy loss (RPL). Moreover, it is expected that this study would give some insights into potential functional mechanisms underlying RPL. (PMID:30348621)
• sgp120 or ITIH4 is cleaved when the contact system is activated and this cleavage could be used as a biomarker in patients with hereditary angioedema with normal C1 inhibitor (PMID:31955064)
• Citrullinated inter-alpha-trypsin inhibitor heavy chain 4 in arthritic joints and its potential effect in the neutrophil migration. (PMID:33238047)
• ITIH4, as an inflammation biomarker, mainly increases in bacterial bloodstream infection. (PMID:33348064)
• Associations between KCNQ1 and ITIH4 gene polymorphisms and infant weight gain in early life. (PMID:34247200)
• ITIH4 is a novel serum biomarker for early gastric cancer diagnosis. (PMID:34687700)
• Longitudinal change of serum inter-alpha-trypsin inhibitor heavy chain H4, and its correlation with inflammation, multiorgan injury, and death risk in sepsis. (PMID:36725250)
• PGK1 modulates balance between pro- and anti-inflammatory cytokines by interacting with ITI-H4. (PMID:36841032)
• Serum ITIH4 in coronary heart disease: a potential anti-inflammatory biomarker related to stenosis degree and risk of major adverse cardiovascular events. (PMID:36891881)
• Hyperglycosylated N-Linked Site 339 of gp120 Appears to Be Unique and May Contribute to CRF01_AE Transmission Among Men Who Have Sex with Men in China and Thailand. (PMID:37335061)
• Serum interalpha-trypsin inhibitor heavy chain H4 may be an anti-inflammatory marker reflecting disease risk, activity and treatment outcome of ankylosing spondylitis. (PMID:38156824)
• Translatome profiling reveals Itih4 as a novel smooth muscle cell-specific gene in atherosclerosis. (PMID:38289873)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Itih4	ENSMUSG00000021922
rattus_norvegicus	Itih4	ENSRNOG00000017381

Paralogs (11): ITIH1 (ENSG00000055957), ITIH6 (ENSG00000102313), PARP4 (ENSG00000102699), VWA5A (ENSG00000110002), ITIH5 (ENSG00000123243), VWA5B2 (ENSG00000145198), ITIH2 (ENSG00000151655), VWA5B1 (ENSG00000158816), ITIH3 (ENSG00000162267), VWA3B (ENSG00000168658), VWA3A (ENSG00000175267)

Protein

Protein identifiers

Inter-alpha-trypsin inhibitor heavy chain H4 — Q14624 (reviewed: Q14624)

Alternative names: Inter-alpha-trypsin inhibitor family heavy chain-related protein, Plasma kallikrein sensitive glycoprotein 120

All UniProt accessions (3): B7ZKJ8, Q14624, H7C0L5

UniProt curated annotations — full annotation on UniProt →

Function. Type II acute-phase protein (APP) involved in inflammatory responses to trauma. May also play a role in liver development or regeneration.

Subunit / interactions. Interacts (via C-terminus) with DNAJC1 (via SANT 2 domain); this interaction protects ITIH4 against cleavage by kallikrein in vitro.

Subcellular location. Secreted.

Tissue specificity. Liver specific.

Post-translational modifications. Cleaved by plasma kallikrein to yield 100 kDa and 35 kDa fragments, and the resulting 100 kDa fragment is further converted to a 70 kDa fragment. N- and O-glycosylated. In urine, O-linked glycosylation on threonine residues in the region from Thr-719 to Thr-725 consists of core 1 or possibly core 8 glycans. Mainly Hex(HexNAc)(2), but also some Hex(3)(HexNAc)(3). N-glycosylated but not O-glycosylated in plasma.

Induction. Levels increase from 1.4 to 3-fold in acute-phase processes such as in acute ischemia stroke (AIS), unstable angina and programmed surgery. In hepatocytes, induced by IL6 but not by other cytokines such as IL1B.

Miscellaneous. Possible biomarker for acute ischemic stroke. Peptides derived from the proline-rich potentially active peptide (PRO_0000016542) may be biomarkers for a variety of disease states including breast cancer.

Similarity. Belongs to the ITIH family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q14624-1	1	yes
Q14624-2	2
Q14624-3	3
Q14624-4	4

RefSeq proteins (2): NP_001159921, NP_002209* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR010600	ITI_HC_C	Domain
IPR013694	VIT	Domain
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR050934	ITIH	Family

Pfam: PF00092, PF06668, PF08487

UniProt features (54 total): sequence conflict 10, glycosylation site 8, helix 8, sequence variant 6, strand 5, splice variant 4, region of interest 3, chain 2, domain 2, turn 2, signal peptide 1, disulfide bond 1, propeptide 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9C4N	ELECTRON MICROSCOPY	2.9
9C4F	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14624-F1	80.71	0.55

Functional residue map

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

Catalytic / active sites (1): 688–689 (cleavage; by kallikrein)

Disulfide bonds (1): 747–925

Glycosylation sites (8): 81, 207, 274, 517, 577, 719, 720, 722

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-109582	Hemostasis
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 174 (showing top): MORF_RAGE, MORF_FLT1, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GNF2_GSTM1, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GNF2_HPN, MORF_ATRX, MORF_ESR1, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_HYALURONAN_METABOLIC_PROCESS, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (3): acute-phase response (GO:0006953), hyaluronan metabolic process (GO:0030212), response to cytokine (GO:0034097)

GO Molecular Function (4): endopeptidase inhibitor activity (GO:0004866), serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (8): extracellular region (GO:0005576), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), platelet dense granule lumen (GO:0031089), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
acute inflammatory response	1
glycosaminoglycan metabolic process	1
response to peptide	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
membrane	1
cell periphery	1
external encapsulating structure	1
secretory granule lumen	1
platelet dense granule	1
extracellular vesicle	1
extracellular region	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2930 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITIH4	CD4	P01730	999
ITIH4	CXCR4	P30991	999
ITIH4	CCR5	P51681	999
ITIH4	CD209	Q9NNX6	998
ITIH4	SCD5	Q86SK9	997
ITIH4	ERVW-1	Q9UQF0	993
ITIH4	PPP2R3C	Q969Q6	972
ITIH4	CLEC4M	Q9H2X3	968
ITIH4	CD207	Q9UJ71	921
ITIH4	DUSP5	Q16690	890
ITIH4	ENPEP	Q07075	884
ITIH4	SLCO2A1	Q92959	877
ITIH4	FN1	P02751	857
ITIH4	CD8A	P01732	848
ITIH4	CXCR5	P32302	843

IntAct

18 interactions, top by confidence:

A	B	Type	Score
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
TP63	ITIH4	psi-mi:“MI:0915”(physical association)	0.370
MAPT	LANCL1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350
RHBDD1	A2ML1	psi-mi:“MI:0914”(association)	0.350
P2RX6	A2ML1	psi-mi:“MI:0914”(association)	0.350
MATN2	IGLL5	psi-mi:“MI:0914”(association)	0.350
UBE2U	IGLL5	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
GRB2	ITIH4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): ITIH4 (Affinity Capture-MS), ITIH4 (Reconstituted Complex), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), SERPING1 (Affinity Capture-MS), C3 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS), ITIH4 (Affinity Capture-MS)

ESM2 similar proteins: A0AAQ4VMX2, A0M8R7, A1X150, I2C090, O02668, P01029, P01030, P01031, P06238, P06684, P08581, P08649, P08650, P0C0L4, P0C0L5, P14046, P16056, P19069, P19823, P28665, P28666, P79263, P97523, P98093, P98094, Q00685, Q03626, Q07DY1, Q07DZ1, Q07E48, Q09YN5, Q108U6, Q14624, Q2IBA6, Q2IBC0, Q2IBD8, Q2IBF2, Q2IBG7, Q2QL89, Q2QLA9

Diamond homologs: A1A5Q7, A6NCI4, Q14624, Q29052, Q3T052, Q3UVV9, A2VE29, A6X935, O02668, P19823, P19827, P56652, P79263, P97278, P97279, P97280, Q06033, Q0VCM5, Q5RB37, Q5RER0, Q61702, Q61703, Q61704, Q63416, Q6UXX5, Q86UX2, Q8BJD1, Q9GLY5, P56651, Q5RJF7, Q8CFG5, Q8IZS8, Q9Z1L5, A8XP97, P34374, Q7Z3S7, Q9ZQ46

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	24
Benign	20

Top pathogenic / likely-pathogenic (0)

SpliceAI

3479 predictions. Top by Δscore:

Variant	Effect	Δscore
3:52817056:CCC:C	acceptor_gain	1.0000
3:52817057:CCC:C	acceptor_gain	1.0000
3:52818413:C:A	donor_gain	1.0000
3:52823555:CCAG:C	donor_gain	1.0000
3:52823848:T:TA	donor_gain	1.0000
3:52824149:C:A	donor_gain	1.0000
3:52824163:T:TA	donor_gain	1.0000
3:52824189:CCCA:C	donor_gain	1.0000
3:52824313:TCCC:T	acceptor_loss	1.0000
3:52824314:CCCT:C	acceptor_loss	1.0000
3:52824316:C:CC	acceptor_gain	1.0000
3:52824393:TTAC:T	donor_loss	1.0000
3:52824394:TA:T	donor_loss	1.0000
3:52824395:A:AC	donor_gain	1.0000
3:52824395:AC:A	donor_gain	1.0000
3:52824395:ACCT:A	donor_gain	1.0000
3:52824395:ACCTC:A	donor_gain	1.0000
3:52824396:C:CG	donor_gain	1.0000
3:52824396:C:CT	donor_gain	1.0000
3:52824396:CC:C	donor_gain	1.0000
3:52824396:CCT:C	donor_gain	1.0000
3:52824396:CCTC:C	donor_gain	1.0000
3:52824396:CCTCC:C	donor_gain	1.0000
3:52824561:CGGGT:C	acceptor_gain	1.0000
3:52824562:GGGT:G	acceptor_gain	1.0000
3:52824563:GGT:G	acceptor_gain	1.0000
3:52824564:GT:G	acceptor_gain	1.0000
3:52824565:TCTG:T	acceptor_loss	1.0000
3:52824566:C:A	acceptor_loss	1.0000
3:52824566:C:CC	acceptor_gain	1.0000

AlphaMissense

6084 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:52824497:G:C	F315L	0.989
3:52824497:G:T	F315L	0.989
3:52824499:A:G	F315L	0.989
3:52829193:A:C	N59K	0.985
3:52829193:A:T	N59K	0.985
3:52824872:G:C	S282R	0.983
3:52824872:G:T	S282R	0.983
3:52824874:T:G	S282R	0.983
3:52829205:G:C	S55R	0.983
3:52829205:G:T	S55R	0.983
3:52829207:T:G	S55R	0.983
3:52826879:A:G	L144P	0.982
3:52826804:A:T	V169D	0.981
3:52826884:A:C	F142L	0.980
3:52826884:A:T	F142L	0.980
3:52826886:A:G	F142L	0.980
3:52829257:A:G	L38P	0.980
3:52824941:A:C	F259L	0.979
3:52824941:A:T	F259L	0.979
3:52824943:A:G	F259L	0.979
3:52826926:G:C	F128L	0.979
3:52826926:G:T	F128L	0.979
3:52826928:A:G	F128L	0.979
3:52829203:C:G	R56P	0.977
3:52821018:A:G	L551P	0.976
3:52824210:G:A	T384I	0.976
3:52824942:A:G	F259S	0.975
3:52823612:C:A	G495W	0.974
3:52824873:C:A	S282I	0.974
3:52829124:G:C	F82L	0.974

dbSNP variants (sampled 300 via entrez): RS1000169200 (3:52828736 G>A,T), RS1000502655 (3:52829917 CA>C), RS1000503680 (3:52825764 C>G,T), RS1000659595 (3:52820401 C>T), RS1000744390 (3:52823416 T>A), RS1000773250 (3:52825432 A>G), RS1001449666 (3:52814696 C>T), RS1001596763 (3:52829339 C>T), RS1001834263 (3:52830643 C>G,T), RS1001939832 (3:52817724 A>C), RS1002042957 (3:52830094 G>A,T), RS1002497244 (3:52830285 A>G,T), RS1002530029 (3:52822360 A>G), RS1002666301 (3:52822618 A>G), RS1002712616 (3:52827914 T>C)

Disease associations

OMIM: gene MIM:600564 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST001241_15	Bipolar disorder	2.000000e-06
GCST001242_6	Schizophrenia	6.000000e-08
GCST001535_1	Immune reponse to smallpox (secreted IL-2)	2.000000e-09
GCST001728_7	Ulcerative colitis	1.000000e-08
GCST002149_14	Schizophrenia	1.000000e-08
GCST002461_4	Body mass index	2.000000e-10
GCST002539_48	Schizophrenia	4.000000e-11
GCST002932_13	Manganese levels	6.000000e-06
GCST004521_123	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004521_201	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004521_203	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004521_259	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST004902_20	Parkinson’s disease	3.000000e-08
GCST006585_2659	Blood protein levels	2.000000e-07
GCST006803_55	Schizophrenia	1.000000e-11
GCST006979_66	Heel bone mineral density	2.000000e-15
GCST007323_99	Risk-taking tendency (4-domain principal component model)	2.000000e-09
GCST007710_4	Anxiety/tension (special factor of neuroticism)	4.000000e-08
GCST008059_19	Estimated glomerular filtration rate	2.000000e-15
GCST008103_3	Bipolar disorder	7.000000e-11
GCST008158_101	Body mass index	2.000000e-06
GCST008478_11	Neurological blood protein biomarker levels	2.000000e-19
GCST009600_27	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	5.000000e-17
GCST010698_14	Subcortical volume (min-P)	8.000000e-09
GCST010699_73	Brain morphology (min-P)	1.000000e-18
GCST010701_137	Cortical surface area (MOSTest)	8.000000e-10
GCST010702_70	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_327	Brain morphology (MOSTest)	1.000000e-10
GCST012226_619	Waist circumference adjusted for body mass index	2.000000e-09
GCST90013406_146	Liver enzyme levels (alkaline phosphatase)	3.000000e-12

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0004340	body mass index
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0009863	anxiety measurement
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004533	alkaline phosphatase measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases methylation, affects cotreatment, affects expression, decreases expression	3
sodium arsenite	decreases expression	2
bisphenol S	affects cotreatment, decreases methylation, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Cadmium	decreases expression, affects binding	2
Aflatoxin B1	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
testosterone undecanoate	increases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
Olanzapine	affects phosphorylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Cholic Acids	affects cotreatment, affects expression	1
Cisplatin	decreases expression	1
Copper	affects binding	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lead	affects binding	1
Mercury	affects expression	1
Nickel	affects binding	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Valproic Acid	decreases expression	1
Zinc	affects binding	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
1-Naphthylisothiocyanate	affects cotreatment, affects expression	1
Zidovudine	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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