HP

Summary

HP (haptoglobin, HGNC:5141) is a protein-coding gene on chromosome 16q22.2, encoding Haptoglobin (P00738). As a result of hemolysis, hemoglobin is found to accumulate in the kidney and is secreted in the urine.

This gene encodes a preproprotein, which is processed to yield both alpha and beta chains, which subsequently combine as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin, while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin. Mutations in this gene and/or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy, the incidence of coronary artery disease in type 1 diabetes, Crohn’s disease, inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson’s disease, and a reduced incidence of Plasmodium falciparum malaria. The protein encoded also exhibits antimicrobial activity against bacteria. A similar duplicated gene is located next to this gene on chromosome 16. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3240 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 86 total — 1 pathogenic
• MANE Select transcript: NM_005143

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5141
Approved symbol	HP
Name	haptoglobin
Location	16q22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000257017
Ensembl biotype	protein_coding
OMIM	140100
Entrez	3240

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 32 protein_coding, 4 retained_intron

ENST00000355906, ENST00000357763, ENST00000398131, ENST00000561927, ENST00000562488, ENST00000562526, ENST00000564499, ENST00000565574, ENST00000565807, ENST00000566821, ENST00000567185, ENST00000567612, ENST00000568417, ENST00000569639, ENST00000570083, ENST00000576168, ENST00000888266, ENST00000888267, ENST00000888268, ENST00000888269, ENST00000888270, ENST00000888271, ENST00000888272, ENST00000888273, ENST00000888274, ENST00000888275, ENST00000888276, ENST00000888277, ENST00000888278, ENST00000888279, ENST00000888280, ENST00000888281, ENST00000888282, ENST00000955432, ENST00000955433, ENST00000955434

RefSeq mRNA: 3 — MANE Select: NM_005143 NM_001126102, NM_001318138, NM_005143

CCDS: CCDS45524, CCDS45525, CCDS82010

Canonical transcript exons

ENST00000355906 — 7 exons

Exon	Start	End
ENSE00002521069	72058254	72058355
ENSE00002586792	72054505	72054657
ENSE00002618960	72060112	72061055
ENSE00003606434	72056530	72056631
ENSE00003608397	72057392	72057466
ENSE00003609326	72056161	72056243
ENSE00003789476	72059114	72059188

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 99.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.0497 / max 2395.7835, expressed in 56 samples.

FANTOM5 promoters (24 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154949	0.9784	10
154960	0.4062	10
154958	0.3657	9
154952	0.3639	13
154959	0.3243	10
154950	0.2502	11
154956	0.1974	10
101743	0.1895	17
154957	0.1711	9
154961	0.1399	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	99.99	gold quality
right lobe of liver	UBERON:0001114	99.98	gold quality
liver	UBERON:0002107	99.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.00	gold quality
parietal pleura	UBERON:0002400	98.55	gold quality
bone marrow	UBERON:0002371	97.99	gold quality
germinal epithelium of ovary	UBERON:0001304	97.25	gold quality
bone marrow cell	CL:0002092	97.03	gold quality
trabecular bone tissue	UBERON:0002483	96.60	gold quality
peritoneum	UBERON:0002358	96.20	gold quality
omental fat pad	UBERON:0010414	96.20	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.10	gold quality
pleura	UBERON:0000977	93.22	gold quality
nasal cavity mucosa	UBERON:0001826	92.85	gold quality
vena cava	UBERON:0004087	92.81	gold quality
colonic epithelium	UBERON:0000397	91.49	gold quality
right atrium auricular region	UBERON:0006631	91.04	gold quality
cardiac atrium	UBERON:0002081	90.83	gold quality
heart right ventricle	UBERON:0002080	90.03	gold quality
monocyte	CL:0000576	89.71	gold quality
coronary artery	UBERON:0001621	89.59	gold quality
left coronary artery	UBERON:0001626	89.37	gold quality
mononuclear cell	CL:0000842	89.04	gold quality
descending thoracic aorta	UBERON:0002345	88.80	gold quality
leukocyte	CL:0000738	88.76	gold quality
blood	UBERON:0000178	88.38	gold quality
right coronary artery	UBERON:0001625	88.06	gold quality
adenohypophysis	UBERON:0002196	87.65	gold quality
trachea	UBERON:0003126	87.43	gold quality
right lung	UBERON:0002167	87.26	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	71913.40
E-HCAD-9	yes	39885.37
E-MTAB-10553	yes	25622.98
E-MTAB-10137	yes	21358.08
E-HCAD-15	yes	8809.83
E-CURD-122	yes	4335.66
E-MTAB-8530	yes	4218.96
E-CURD-112	yes	8.53
E-MTAB-9801	yes	6.89
E-MTAB-6386	no	70.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPA, CEBPB, CEBPD, CEBPE, CEBPG, CREB3, CTBP2, DBP, ELF3, GATA4, GRHL3, HIF1A, HIVEP1, HNF1B, HNF4A, JUN, KLF11, KLF3, MEF2A, MITF, NFATC1, NFATC2, NFKB1, NFKB, NR1I2, NR3C1, NR5A1, PDX1, PPARG, RAI1, RELB, SMAD4, SOX17, SP1, SP3, SPI1, STAT3, STAT5B, TCF3

miRNA regulators (miRDB)

5 targeting HP, 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-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6715B-3P	98.80	68.07	1204
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-1247-5P	85.92	61.07	65

Literature-anchored findings (GeneRIF, showing 40)

• genotype as a risk factor for postmenopausal osteoporosis (PMID:11565553)
• Hp may be regarded as a regulator of the Th1/Th2 balance in both human and murine immune systems. (PMID:11865978)
• Hp-mediated haemoglobin catabolism in lung cells may be an efficient mechanism to reduce oxidative damage associated with haemolysis (PMID:11865979)
• haptoglobin-dependent HbSR/CD163 scavenging system for hemoglobin clearance prevents toxic effects of hemoglobin in plasma and kidney (PMID:11865982)
• genotype and diabetic microangiopathies in Japanese diabetic patients (PMID:12187922)
• study shows that haptoglobin adheres to peritoneal macrophages; decreases adhesion, which may influence phagocytic function; and up-regulates IL-6 production (PMID:12372461)
• propose that an Hp-mediated hemoglobin catabolism process exists in alveolar macrophages; this process is likely coupled to an iron mobilization pathway and may be an efficient mechanism to reduce oxidative damage associated with hemolysis (PMID:12388365)
• Storage iron, haptoglobin 2-2, and elevated alpha 1-Antichymotrypsin are independent positive predictors of HIV-1 viral load (PMID:12792358)
• smokers with Hp 2-2 phenotype have a decreased antioxidant capacity suggesting that smoking coupled with the inheritance of an Hp-2-2 type predispose to more oxidative stress and cardiovascular disease (PMID:12867276)
• Allele is associated with 30-day mortality in diabetics with acute myocardial infarction. (PMID:12941748)
• The analysis involved the data on nine polymorphic codominant loci: HP, GC, TF, PI, PGM1, GLO1, C3, ACP1, and ESD. The loci were selected by significance of differences in genotype frequencies between tuberculosis patients and healthy controls (PMID:12942785)
• Our results suggest that the haptoglobin phenotype has no effect on the prevalence of exudative AMD (age-related macular degeneration). (PMID:14597045)
• Haptoglobin homozygosity seems to represent a possible risk factor for CRF in hypertensive, diabetic and PKD patients (PMID:14629808)
• the amount of haptoglobin released by human adipose tissue explants in primary culture was quite low in relationship to the circulating level of haptoglobin (PMID:14657203)
• This report provides a simple protocol that can be used to purify each Hp phenotype (PMID:14711515)
• pattern of haptoglobin phenotype distribution in breast cancer patients is family history-dependent (PMID:14967153)
• Findings that both Hp1-1 and Hp2-2 haptoglobin phenotypes inhibit oxidation of low-density lipoprotein components, albeit to a different degree, provide a molecular basis for Hp2-2 atherogenic properties. (PMID:15049697)
• Data demonstrate that haptoglobin is an extremely potent antioxidant, which directly protects low density lipoprotein from Cu(2+)-induced oxidation. (PMID:15274115)
• Serum ferritin concentration and Hp polymorphism are independently associated with circulating oxLDL levels in males (PMID:15306193)
• Hp phenotype is an apparent risk factor for the development of gestational diabetes. (PMID:15333469)
• coexpression of the proform of Hp (proHp) and C1r-LP effected cleavage of proHp in the endoplasmic reticulum (PMID:15385675)
• subjects carrying the Hp*1/*1 genotype, that has the lowest molecular size and diffuses more readily in the interstitial cerebral fluid, are more protected against idiopathic generalized epilepsy than those with other haptoglobin genotypes (PMID:15490286)
• Women with endometriosis have higher peritoneal fluid and plasma expression levels of haptoglobin beta chain isoform E (molecular weight, 38.40 +/- 0.94 kD; and isoelectric point, 5.63 +/- 0.17). (PMID:15866595)
• Haptoglobin expression by retrogradely shed endometrial tissues in peritoneal fluid supports a mechanism whereby these purported precursors of endometriotic lesions escape immune destruction. (PMID:16009149)
• Haptoglobin is an extracellular holdase-type chaperone (PMID:16086594)
• Hp inhibits precipitation of stressed proteins by forming solubilized complexes with them, cannot protect enzymes from heat-induced loss of function, and lacks ATPase activity and the ability to independently refold proteins following stresses (PMID:16086594)
• Haptoglobins containing the alpha2 subunit seem to be associated with a higher rate of vasospasm than is haptoglobin alpha1-alpha1. (PMID:16436647)
• a human haptoglobin polymorphism has a role in oxidative stress induced by free hemoglobin on red blood cells (PMID:16681422)
• Haptoglobin polymorphism was associated with more severe hypertension and proteinuria in patients with preeclampsia. (PMID:16879055)
• reverse cholesterol transport is decreased in Hp2-2 genotype (PMID:17082477)
• Structural modeling based on the well characterized serine protease domain fold suggests that this sequence represents a loop extension unique for haptoglobin (PMID:17102136)
• no significant differences were observed for the three Hp genotypes; this polymorphism is not associated with the presence of diabetic retinopathy in the Brazilian population (PMID:17275123)
• CD163-mediated Hb-Hp uptake by peripheral blood monocytes constitutes an Hb-Hp clearance pathway, which acts at the site of intravascular hemolysis to reduce Hb-Hp circulation time and toxicity (PMID:17460152)
• Individuals with diabetes mellitus and a haptoglobin 2.2 genotype demonstrate lower CD163 scavenger receptor levels and an impaired hemoglobin clearance capacity, with increased incidence of myocardial infarction. (PMID:17525367)
• Women homozygous for haptoglobin with low ACP1 activity are more likely to conceive in the first part of the year. Women heterozygous for haptoglobin with medium-high ACP1 activity are more likely to conceive in the last part of the year. (PMID:17678914)
• Congenital haptoglobin deficiency caused by Hp(del) homozygosity is presumed to be present in Thailand as a risk factor for anaphylactic transfusion reactions with a frequency similar to that in Japan. (PMID:17764509)
• Gene deletion is present in Eastern Asians (Japanese, Chinese and Koreans) (PMID:17880628)
• that interactions between C/EBPs and HDAC1 negatively regulate C/EBPdelta-dependent haptoglobin expression in intestinal epithelial cells. (PMID:17910034)
• the association of haptoglobin genotypes with the risk of Parkinson’s disease. (PMID:17918239)
• The extracellular chaperone haptoglobin is likely to help control amyloid formation and toxicity in vivo (PMID:18075673)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hp	ENSMUSG00000031722
rattus_norvegicus	Hp	ENSRNOG00000014964
drosophila_melanogaster	CG31266	FBGN0051266
drosophila_melanogaster	CG31267	FBGN0051267

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HPR (ENSG00000261701)

Protein

Protein identifiers

Haptoglobin — P00738 (reviewed: P00738)

Alternative names: Zonulin

All UniProt accessions (10): A0A0C4DGL8, P00738, H0Y300, H3BMJ7, H3BS21, J3KRH2, J3KSV1, J3QLC9, J3QQI8, J3QR68

UniProt curated annotations — full annotation on UniProt →

Function. As a result of hemolysis, hemoglobin is found to accumulate in the kidney and is secreted in the urine. Haptoglobin captures, and combines with free plasma hemoglobin to allow hepatic recycling of heme iron and to prevent kidney damage. Haptoglobin also acts as an antioxidant, has antibacterial activity, and plays a role in modulating many aspects of the acute phase response. Hemoglobin/haptoglobin complexes are rapidly cleared by the macrophage CD163 scavenger receptor expressed on the surface of liver Kupfer cells through an endocytic lysosomal degradation pathway. The uncleaved form of allele alpha-2 (2-2), known as zonulin, plays a role in intestinal permeability, allowing intercellular tight junction disassembly, and controlling the equilibrium between tolerance and immunity to non-self antigens.

Subunit / interactions. Tetramer of two alpha and two beta chains; disulfide-linked. The hemoglobin/haptoglobin complex is composed of a haptoglobin dimer bound to two hemoglobin alpha-beta dimers. Interacts with CD163. Interacts with ERGIC3.

Subcellular location. Secreted.

Tissue specificity. Expressed by the liver and secreted in plasma.

Disease relevance. Anhaptoglobinemia (AHP) [MIM:614081] A condition characterized by the absence of the serum glycoprotein haptoglobin. Serum levels of haptoglobin vary among normal persons: levels are low in the neonatal period and in the elderly, differ by population, and can be influenced by environmental factors, such as infection. Secondary hypohaptoglobinemia can occur as a consequence of hemolysis, during which haptoglobin binds to free hemoglobin. Congenital haptoglobin deficiency is a risk factor for anaphylactic non-hemolytic transfusion reactions. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. In human populations there are two major allelic forms, alpha-1 (1-1) with 83 residues and alpha-2 (2-2) with 142 residues. These alleles determine 3 possible genotypes, homozygous (1-1 or 2-2) and heterozygous (2-1), and 3 major phenotypes HP1F/HP1S and HP2FS. The two main alleles of HP1 are called HP1F (fast) and HP1S (slow). The alleles exhibit different oligomerization properties. In healthy males, but not in females, the Hp 2-2 phenotype is associated with higher serum iron, decreased antimicrobial and antioxidant capability, and less efficient clearance from the circulation, than Hp 1-1 and 2-1. The sequence displayed in this entry corresponds to allele alpha-2 (2-2).

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P00738-1	1	yes
P00738-2	2

RefSeq proteins (3): NP_001119574, NP_001305067, NP_005134* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR043504

Pfam: PF00089

UniProt features (63 total): strand 23, disulfide bond 7, helix 7, turn 6, sequence variant 5, glycosylation site 4, chain 3, domain 3, sequence conflict 2, signal peptide 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
4X0L	X-RAY DIFFRACTION	2.05
9FNM	X-RAY DIFFRACTION	2.52
9HEJ	ELECTRON MICROSCOPY	2.82
5HU6	X-RAY DIFFRACTION	2.9
6TB2	X-RAY DIFFRACTION	2.9
8XMW	ELECTRON MICROSCOPY	2.94
4WJG	X-RAY DIFFRACTION	3.1
8XMP	ELECTRON MICROSCOPY	3.11
9HEK	ELECTRON MICROSCOPY	3.15
8XMQ	ELECTRON MICROSCOPY	3.21
9NB6	ELECTRON MICROSCOPY	3.3
9FHB	ELECTRON MICROSCOPY	3.87
9NB8	ELECTRON MICROSCOPY	4
9FMU	ELECTRON MICROSCOPY	4.46
9FNO	ELECTRON MICROSCOPY	5.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00738-F1	85.21	0.57

Functional residue map

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

Disulfide bonds (7): 33, 52–86, 92, 111–145, 149–266, 309–340, 351–381

Glycosylation sites (4): 211, 241, 184, 207

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2168880	Scavenging of heme from plasma
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 0 (showing top):

GO Biological Process (10): immune system process (GO:0002376), defense response (GO:0006952), acute-phase response (GO:0006953), inflammatory response (GO:0006954), zymogen activation (GO:0031638), response to hydrogen peroxide (GO:0042542), defense response to bacterium (GO:0042742), negative regulation of hydrogen peroxide catabolic process (GO:2000296), proteolysis (GO:0006508), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), antioxidant activity (GO:0016209), hemoglobin binding (GO:0030492), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), haptoglobin-hemoglobin complex (GO:0031838), specific granule lumen (GO:0035580), extracellular exosome (GO:0070062), endocytic vesicle lumen (GO:0071682), blood microparticle (GO:0072562), tertiary granule lumen (GO:1904724)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Binding and Uptake of Ligands by Scavenger Receptors	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	2
cellular anatomical structure	2
intracellular organelle lumen	2
biological_process	1
response to stress	1
acute inflammatory response	1
protein processing	1
response to reactive oxygen species	1
response to bacterium	1
negative regulation of catabolic process	1
negative regulation of hydrogen peroxide metabolic process	1
hydrogen peroxide catabolic process	1
regulation of hydrogen peroxide catabolic process	1
protein metabolic process	1
cellular detoxification	1
endopeptidase activity	1
serine-type peptidase activity	1
molecular_function	1
cellular oxidant detoxification	1
protein binding	1
binding	1
protein-containing complex	1
secretory granule lumen	1
specific granule	1
extracellular vesicle	1
endocytic vesicle	1
extracellular region	1
tertiary granule	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

99 interactions, top by confidence:

A	B	Type	Score
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
HP	APOE	psi-mi:“MI:0915”(physical association)	0.680
APOE	HP	psi-mi:“MI:0407”(direct interaction)	0.680
HP	APOE	psi-mi:“MI:0407”(direct interaction)	0.680
RPL10A	RRP8	psi-mi:“MI:0914”(association)	0.640
APOA1	HP	psi-mi:“MI:0407”(direct interaction)	0.560
DDX31	IGLL5	psi-mi:“MI:0914”(association)	0.530
ICE2	HP	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
HP	ERGIC3	psi-mi:“MI:0915”(physical association)	0.520
ERGIC3	HP	psi-mi:“MI:0915”(physical association)	0.520
HP	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
MIS12	C1 segment	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
SMAD3	HP	psi-mi:“MI:0915”(physical association)	0.370
RPL11	HP	psi-mi:“MI:0915”(physical association)	0.370
HP	TBL1X	psi-mi:“MI:0915”(physical association)	0.370
TGM2	HP	psi-mi:“MI:0915”(physical association)	0.370
HP	TP63	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (119): HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), APOA1 (Protein-peptide), HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), HP (Affinity Capture-MS), ERGIC3 (Affinity Capture-Western), HP (Affinity Capture-MS)

ESM2 similar proteins: A6MFK7, A6MFK8, B5G6G5, B6D985, B6E141, O35086, P00738, P00739, P00740, P00741, P05156, P06866, P06869, P16294, P19006, P19007, P19540, P25155, P29598, P50417, P81428, P82807, P83370, P98119, Q1JRP2, Q1L658, Q1L659, Q28801, Q2TBU0, Q4QXT9, Q56VR3, Q58L93, Q58L94, Q58L95, Q58L96, Q5R5F6, Q5S248, Q5VAN1, Q60574, Q61646

Diamond homologs: A0A1D5NSM8, A2AVA0, B6D985, B6E141, O35086, P00736, P00738, P00739, P00743, P06866, P09871, P15156, P19006, P19007, P43430, P50417, P57727, P70375, P80010, Q0VCX1, Q28801, Q2TBU0, Q3UZ09, Q4R577, Q5R1W3, Q5R544, Q5R5F6, Q5VAN1, Q60574, Q61646, Q62558, Q69DK8, Q6IE14, Q6IE64, Q6P6T1, Q7SZE1, Q8CFG8, Q8CFG9, Q8CG14, Q8CG16

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
HP	“down-regulates quantity”	HBB	binding
HP	“down-regulates quantity”	HBA1	binding
HP	“up-regulates quantity by stabilization”	APOA1	binding
HP	“form complex”	hb:hp	binding
C1RL	“up-regulates activity”	HP	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	51
Likely benign	17
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
15899	NG_012651.1:g.=	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2666 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:72060687:T:A	C340S	0.999
16:72060688:G:C	C340S	0.999
16:72060192:T:A	W175R	0.998
16:72060192:T:C	W175R	0.998
16:72060194:G:C	W175C	0.998
16:72060194:G:T	W175C	0.998
16:72060594:T:A	C309S	0.998
16:72060595:G:C	C309S	0.998
16:72060259:T:C	L197P	0.997
16:72060415:T:C	L249P	0.997
16:72060521:G:C	W284C	0.997
16:72060521:G:T	W284C	0.997
16:72060687:T:C	C340R	0.997
16:72060688:G:A	C340Y	0.997
16:72060594:T:C	C309R	0.996
16:72060689:T:G	C340W	0.996
16:72060720:T:A	C351S	0.996
16:72060721:G:A	C351Y	0.996
16:72060721:G:C	C351S	0.996
16:72060863:G:C	W398C	0.996
16:72060863:G:T	W398C	0.996
16:72060596:C:G	C309W	0.995
16:72060738:A:C	S357R	0.995
16:72060740:T:A	S357R	0.995
16:72060740:T:G	S357R	0.995
16:72060255:T:A	W196R	0.994
16:72060255:T:C	W196R	0.994
16:72060519:T:A	W284R	0.994
16:72060519:T:C	W284R	0.994
16:72060522:G:T	G285W	0.994

dbSNP variants (sampled 300 via entrez): RS1000244518 (16:72054489 T>C,G), RS1000427142 (16:72060967 G>A), RS1000636449 (16:72055702 T>C), RS1001310303 (16:72061481 A>G), RS1001693061 (16:72055171 C>T), RS1002207449 (16:72054972 T>C), RS1002223412 (16:72053289 C>A,T), RS1003654226 (16:72058725 C>T), RS1004256881 (16:72054187 G>T), RS1004267201 (16:72060479 G>A,C), RS1005013215 (16:72052621 T>A,C), RS1005429775 (16:72056209 A>C), RS1005506763 (16:72055225 C>T), RS1005896456 (16:72056420 C>A,G,T), RS1007455621 (16:72054229 C>T)

Disease associations

OMIM: gene MIM:140100 | disease phenotypes: MIM:614081

GenCC curated gene-disease

Mondo (2): anhaptoglobinemia (MONDO:0013564), breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects expression, decreases expression, increases expression	4
bisphenol A	increases expression, affects cotreatment, decreases expression, affects expression	3
Dexamethasone	increases expression, affects cotreatment, decreases expression	3
Nickel	affects binding, increases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
Ascorbic Acid	affects activity, affects response to substance	2
Benzo(a)pyrene	decreases expression	2
Hydrogen Peroxide	affects cotreatment, affects response to substance, decreases expression	2
Lead	affects binding, increases expression	2
Silicon Dioxide	increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Asian ginseng	decreases expression, decreases reaction	1
perfluorodecanesulfonic acid	increases expression	1
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
benazol P	affects expression	1
lariciresinol	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
alclofenac	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
WAY-169916	increases expression, decreases reaction	1
bisphenol S	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	affects binding	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery