AHSG

Summary

AHSG (alpha 2-HS glycoprotein, HGNC:349) is a protein-coding gene on chromosome 3q27.3, encoding Alpha-2-HS-glycoprotein (P02765). Promotes endocytosis, possesses opsonic properties and influences the mineral phase of bone.

The protein encoded by this gene is a negatively-charged serum glycoprotein that is synthesized by hepatocytes. The encoded protein consists of two polypeptide chains, which are both cleaved from a proprotein encoded from a single mRNA. It is involved in several processes, including endocytosis, brain development, and the formation of bone tissue. Defects in this gene are a cause of susceptibility to leanness.

Source: NCBI Gene 197 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alopecia-intellectual disability syndrome 1 (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 80 total — 1 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• MANE Select transcript: NM_001622

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:349
Approved symbol	AHSG
Name	alpha 2-HS glycoprotein
Location	3q27.3
Locus type	gene with protein product
Status	Approved
Aliases	FETUA, A2HS, HSGA
Ensembl gene	ENSG00000145192
Ensembl biotype	protein_coding
OMIM	138680
Entrez	197

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 21 protein_coding, 1 retained_intron

ENST00000273784, ENST00000411641, ENST00000478441, ENST00000864079, ENST00000864080, ENST00000864081, ENST00000864082, ENST00000864083, ENST00000864084, ENST00000864085, ENST00000864086, ENST00000864087, ENST00000864088, ENST00000864089, ENST00000864090, ENST00000864091, ENST00000864092, ENST00000864093, ENST00000864094, ENST00000864095, ENST00000864096, ENST00000864097

RefSeq mRNA: 4 — MANE Select: NM_001622 NM_001354571, NM_001354572, NM_001354573, NM_001622

CCDS: CCDS3278, CCDS87176

Canonical transcript exons

ENST00000411641 — 7 exons

Exon	Start	End
ENSE00000969148	186617187	186617350
ENSE00000969149	186618536	186618637
ENSE00001079628	186619857	186619940
ENSE00001607994	186613060	186613354
ENSE00001700050	186620586	186621318
ENSE00003612395	186616443	186616527
ENSE00003671180	186615685	186615795

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 99.83.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 28.9125 / max 14222.6351, expressed in 122 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40271	28.9125	122

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	99.83	gold quality
right lobe of liver	UBERON:0001114	99.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.14	gold quality
sperm	CL:0000019	79.37	gold quality
male germ cell	CL:0000015	79.10	gold quality
tongue squamous epithelium	UBERON:0006919	76.39	silver quality
type B pancreatic cell	CL:0000169	74.65	gold quality
olfactory bulb	UBERON:0002264	74.46	gold quality
heart right ventricle	UBERON:0002080	73.07	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	72.66	gold quality
adrenal tissue	UBERON:0018303	71.52	gold quality
buccal mucosa cell	CL:0002336	71.46	silver quality
hair follicle	UBERON:0002073	70.96	silver quality
cervix squamous epithelium	UBERON:0006922	69.34	gold quality
vena cava	UBERON:0004087	69.33	silver quality
superficial temporal artery	UBERON:0001614	68.53	gold quality
endothelial cell	CL:0000115	67.66	silver quality
epithelium of nasopharynx	UBERON:0001951	66.06	silver quality
epithelial cell of pancreas	CL:0000083	65.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	65.82	gold quality
tendon of biceps brachii	UBERON:0008188	64.81	gold quality
embryo	UBERON:0000922	64.33	gold quality
mammary duct	UBERON:0001765	64.11	gold quality
epithelium of mammary gland	UBERON:0003244	63.98	gold quality
thymus	UBERON:0002370	63.89	gold quality
nasal cavity epithelium	UBERON:0005384	63.68	gold quality
mucosa of urinary bladder	UBERON:0001259	63.62	gold quality
myocardium	UBERON:0002349	63.05	gold quality
diaphragm	UBERON:0001103	63.02	gold quality
quadriceps femoris	UBERON:0001377	62.41	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	32187.07
E-GEOD-130473	yes	22950.68
E-MTAB-6701	yes	16555.04
E-MTAB-7407	yes	15234.68
E-HCAD-9	yes	55.55
E-MTAB-10553	yes	37.60
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, CEBPG, DNMT1, FOXA2, ID1, MYC, PITX2

miRNA regulators (miRDB)

13 targeting AHSG, 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-8063	99.91	69.76	3146
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-1248	98.47	67.54	1314

Literature-anchored findings (GeneRIF, showing 40)

• Plasma alpha2-HS glycoprotein concentrations in patients with acute myocardial infarction quantified by a modified ELISA. (PMID:11922920)
• AHSG along with these cytokines may also negatively regulate neonatal skeletal development. (PMID:12153747)
• AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes (PMID:12153747)
• REVIEW: an important inhibitor of pathologic calcification, and deficiency contributes to pathogenesis of cardiovascular calcifications in dialysis patients. (PMID:12207096)
• This protein inhibits calcification by inhibiting the formation of colloidal calcium-protein particles. (PMID:12556469)
• Our data provided no evidence to support the AHSG gene as a quantitative trait locus (QTL) for the bone mineral density (BMD) variation in a Chinese population. (PMID:14667137)
• Proportion of noncarriers of AHSG 2 allele significantly higher in women with endometriosis than in women without. Women not carrying AHSG 2 allele were found to have twice the risk of endometriosis than those carrying at least one copy of this allele. (PMID:15589849)
• AHSG levels demonstrated a significant negative correlation with free phosphate levels (P<0.001), indicating that AHSG is a novel determinant of serum phosphate. (PMID:15592877)
• This protein is associated with insulin-mediated inhibition of lipolysis. (PMID:15599699)
• common variant of AHSG, previously associated with a lower AHSG protein level, is more common among lean than obese and overweight men, supporting the results from Ahsg knock-out mice, namely, that AHSG modulates body mass (PMID:15806395)
• Deficiencies of calcification inhibitors such as fetuin-A are relevant pathomechanisms in the progression of uncontrolled vascular calcification and may offer potential for future therapeutic approaches. (PMID:15931001)
• These results suggest that the AHSG gene polymorphism may be associated with late-onset Alzheimer disease in Italians. Additional studies are warranted to examine the biological relevance of AHSG in neurodegenerative disorders. (PMID:16002217)
• We conclude that a common variation (Thr230Met) in the AHSG gene is associated with a marked increase in beta2-adrenoceptor sensitivity in subcutaneous fat cells, which may be of importance in body weight regulation. (PMID:16024912)
• major allele of a synonymous coding single nucleotide polymorphism (SNP) in exon 7 of alpha2-Heremans-Schmid glycoprotein (AHSG)presented significant evidence of association with type 2 diabetes (PMID:16046317)
• Fetuin-A is necessary for a robust infection by malarial sporozoites; its interaction with P. berghei thrombospondin-related adhesive protein (TRAP) enhances the parasite’s ability to invade human hepatocytes in vitro (PMID:16113307)
• A total of 45% of participants (80 of 177) in the highest quartile of fetuin-A had metabolic syndrome X compared with 24% of participants (42 of 177) in the lowest quartile. (PMID:16567568)
• Fetuin A, 59 kDa protein, produced in the liver is a circulating inhibitor of vascular calcification (PMID:16898488)
• There is an independent and significant association between reduced serum fetuin-A levels and multi-site cardiovascular calcification in hemodialysis. (PMID:16968979)
• alpha2-Heremans-Schmid glycoprotein/fetuin may have a role in atherosclerotic vascular disease and low bone mass (PMID:17010978)
• the AHSG gene may be linked to bone geometry in Caucasians, but not in Chinese (PMID:17303000)
• low serum fetuin A levels in chronic kidney disease (CKD) may contribute to impaired endothelial functions in CKD (PMID:17318070)
• Finds polymorphisms in the AHSG gene may have effects on BMD variation in spine and hip of Caucasian population suggesting possible effects on osteoporosis. (PMID:17557141)
• Role of fetuin-A in the pathogenesis calcific aortic valve stenosis independently of the renal function. (PMID:17611637)
• Fetuin-A is an important predictor of death at 6 months in STEMI patients independent of NT-proBNP, CRP, and CADILLAC risk score. (PMID:17702860)
• CKD patients on hemodialysis have similar the reduction in serum fetuin-A levels in Italian HD patients is not associated with an alteration in the distribution of AHSG T256S polymorphisms. (PMID:17851232)
• Serum fetuin-A levels are not related to all-cause or cardiovascular mortality among persons with predominantly non-diabetic stage 3 or 4 chronic kidney disease. (PMID:17882149)
• A single nucleotide polymorphism in the promoter affects AHSG gene transcription, possibly by producing different association with AP-1. (PMID:17889958)
• FETUA may contribute to scarless wound healing (PMID:17960182)
• Prominent defects in glycosylation/sialylation of fetuin-A revealed by this study might be responsible for impaired function of fetuin-A, leading to deficient fetal growth. (PMID:18065755)
• Low fetuin-A level is a useful predictor of malnutrition and inflammation, as well as being a useful predictor of the cardiac failure caused by an increased ventricular load in hemodialysis patients. (PMID:18085392)
• In hemodialysis patients, lower fetuin-A concentrations were associated with increases in both cardiovascular and overall mortality. (PMID:18089450)
• Serum AHSG concentration, measured before starting treatment, predicts survival in patients with glioblastoma. (PMID:18281421)
• Circulating levels of MGP and fetuin-A could not be identified as independent predictors of vascular stiffness or other carotid artery parameters in pediatric renal transplant recipients. (PMID:18286307)
• Common variations in AHSG may contribute to the interindividual variation in metabolic traits in type 2 diabetes and dyslipidemia. (PMID:18316360)
• These data in a selected cohort of CKD patients indicate that fetuin-A may be one of the contributing factors for the development of endothelial dysfunction in CKD patients. (PMID:18334823)
• provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans (PMID:18335040)
• fetuin-A and other acidic bulk plasma proteins may be considered as mineral chaperones mediating the stabilization, safe transport, and clearance in the body of calcium and phosphate as colloidal complexes, thus, preventing ectopic calcification (PMID:18364352)
• Among well-functioning older persons, serum fetuin-A is associated with incident diabetes mellitus, independent of other markers of insulin resistance. (PMID:18612115)
• Data suggest that fetuin-A is an independent risk factor of type 2 diabetes. (PMID:18633113)
• Fetuin-A levels are higher in obese children with non-alcoholic fatty liver disease, and are related to insulin resistance and to features of metabolic syndrome X in both cross-sectional and longitudinal analyses (PMID:18728159)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ahsg2	ENSDARG00000069293
mus_musculus	Ahsg	ENSMUSG00000022868
rattus_norvegicus	Ahsg	ENSRNOG00000038370

Paralogs (3): FETUB (ENSG00000090512), KNG1 (ENSG00000113889), HRG (ENSG00000113905)

Protein

Protein identifiers

Alpha-2-HS-glycoprotein — P02765 (reviewed: P02765)

Alternative names: Alpha-2-Z-globulin, Ba-alpha-2-glycoprotein, Fetuin-A

All UniProt accessions (2): C9JV77, P02765

UniProt curated annotations — full annotation on UniProt →

Function. Promotes endocytosis, possesses opsonic properties and influences the mineral phase of bone. Shows affinity for calcium and barium ions.

Subunit / interactions. Alpha-2-HS glycoprotein derives from this precursor, when the connecting peptide is cleaved off. The two chains A and B are held together by a single disulfide bond.

Subcellular location. Secreted.

Tissue specificity. Synthesized in liver and selectively concentrated in bone matrix. Secreted in plasma. It is also found in dentin in much higher quantities than other plasma proteins.

Post-translational modifications. Phosphorylated by FAM20C in the extracellular medium. O- and N-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. N-glycan at Asn-156: Hex5HexNAc4; N-glycan heterogeneity at Asn-176: Hex5HexNAc4 (major) and Hex6HexNAc5 (minor).

Disease relevance. Alopecia-intellectual disability syndrome 1 (APMR1) [MIM:203650] A rare autosomal recessive form of alopecia. APMR1 patients show loss of hair on the scalp, absence of eyebrows, eyelashes, axillary and pubic hair, and mild to severe intellectual disability. The disease may be caused by variants affecting the gene represented in this entry.

Polymorphism. There are two common alleles, AHSG1 and AHSG2. AHSG1 has Thr-248/Thr-256; AHSG2 has Met-248/Ser-256.

Similarity. Belongs to the fetuin family.

RefSeq proteins (4): NP_001341500, NP_001341501, NP_001341502, NP_001613* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR001363	Prot_inh_fetuin_CS	Conserved_site
IPR025760	Cystatin_Fetuin_A	Domain
IPR046350	Cystatin_sf	Homologous_superfamily
IPR050735	Kininogen_Fetuin_HRG	Family

Pfam: PF00031

UniProt features (40 total): glycosylation site 8, modified residue 7, disulfide bond 6, sequence variant 6, sequence conflict 5, chain 2, domain 2, signal peptide 1, propeptide 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02765-F1	77.59	0.56

Functional residue map

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

Post-translational modifications (7): 138, 319, 325, 328, 330, 134, 135

Disulfide bonds (6): 32–358, 89–100, 114–132, 146–149, 208–219, 230–247

Glycosylation sites (8): 156, 176, 270, 280, 293, 339, 341, 346

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-6798695	Neutrophil degranulation
R-HSA-8957275	Post-translational protein phosphorylation

MSigDB gene sets: 221 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_PINOCYTOSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, MODULE_45, GNF2_HPN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_16

GO Biological Process (9): skeletal system development (GO:0001501), ossification (GO:0001503), pinocytosis (GO:0006907), acute-phase response (GO:0006953), regulation of bone mineralization (GO:0030500), negative regulation of bone mineralization (GO:0030502), negative regulation of insulin receptor signaling pathway (GO:0046627), regulation of inflammatory response (GO:0050727), positive regulation of phagocytosis (GO:0050766)

GO Molecular Function (4): endopeptidase inhibitor activity (GO:0004866), cysteine-type endopeptidase inhibitor activity (GO:0004869), kinase inhibitor activity (GO:0019210), protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Metabolism of proteins	1
Innate Immune System	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bone mineralization	2
cellular anatomical structure	2
system development	1
multicellular organismal process	1
endocytosis	1
acute inflammatory response	1
regulation of ossification	1
regulation of biomineral tissue development	1
negative regulation of ossification	1
regulation of bone mineralization	1
negative regulation of biomineral tissue development	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
kinase activity	1
kinase regulator activity	1
binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
external encapsulating structure	1
platelet alpha granule	1
secretory granule lumen	1
secretory granule	1
cytoplasmic vesicle lumen	1

Protein interactions and networks

STRING

3223 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AHSG	ALB	P02768	991
AHSG	TLR4	O00206	988
AHSG	MGP	P08493	977
AHSG	SERPINA1	P01009	913
AHSG	SPP2	Q13103	899
AHSG	ORM1	P02763	881
AHSG	GC	P02774	870
AHSG	HRG	P04196	863
AHSG	ANXA2	P07355	849
AHSG	ORM2	P19652	849
AHSG	HP	P00737	845
AHSG	SPP1	P10451	835
AHSG	KNG1	P01042	832
AHSG	ST6GALNAC2	Q9UJ37	825
AHSG	ST6GALNAC4	Q9H4F1	825

IntAct

75 interactions, top by confidence:

A	B	Type	Score
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
CDK5	FIBP	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
AHSG	POTEF	psi-mi:“MI:0915”(physical association)	0.590
Mad2l1	BUB1B	psi-mi:“MI:0915”(physical association)	0.560
CA8	IGLL5	psi-mi:“MI:0914”(association)	0.530
DDX31	IGLL5	psi-mi:“MI:0914”(association)	0.530
USP38	AHSG	psi-mi:“MI:0914”(association)	0.530
PDPK1	AGRN	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
FAM20C	AHSG	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
RAB11A	LANCL1	psi-mi:“MI:2364”(proximity)	0.420
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
ABL1	AHSG	psi-mi:“MI:0915”(physical association)	0.400
Hsd17b7	AHSG	psi-mi:“MI:0915”(physical association)	0.400
Smad3	AHSG	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
AHSG	HLA-DPB1	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
ALB	F2	psi-mi:“MI:0914”(association)	0.350
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
SOD1	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
SNX27	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (128): AHSG (Affinity Capture-MS), POTEF (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), POTEF (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), AHSG (Affinity Capture-MS), FBXW7 (Affinity Capture-Western)

ESM2 similar proteins: A0A1S3PBB7, B6S2X0, O08677, O70159, P01042, P01044, P01045, P01048, P02765, P08932, P08934, P12763, P24090, P25230, P29695, P29699, P29700, P29701, P33046, P49928, P49929, P49931, P51437, P54229, P80191, P97515, Q1KLX0, Q1KLX3, Q1KLX5, Q1KLX6, Q1KLX7, Q1KLX9, Q1KLY0, Q1KLY2, Q1KLY4, Q1KLY6, Q1KLY7, Q1KLY8, Q58D62, Q5KQS1

Diamond homologs: O70159, P02765, P12763, P24090, P29695, P29699, P29700, P29701, P80191, P97515, Q5KQS1, Q5KQS2, Q5KQS3, Q5KQS4, Q5KQS5, Q9DGI0, Q9N2D0, Q9QX79, Q58D62, Q9UGM5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOXA2	“up-regulates quantity by expression”	AHSG	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
FCGR3A-mediated phagocytosis	5	15.1×	3e-03
Activation of STAT3 by cadherin engagement	5	13.2×	4e-03
FCERI mediated NF-kB activation	5	12.6×	4e-03
Downstream TCR signaling	6	12.4×	2e-03
Platelet activation, signaling and aggregation	7	11.9×	6e-04
CLEC7A (Dectin-1) signaling	5	11.5×	5e-03
MAPK6/MAPK4 signaling	5	11.0×	5e-03
ABC-family protein mediated transport	5	9.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein localization to plasma membrane	5	15.6×	9e-03
protein phosphorylation	9	7.0×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	50
Likely benign	9
Benign	15

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
488189	NM_001622.4(AHSG):c.950G>A (p.Arg317His)	Likely pathogenic

SpliceAI

1089 predictions. Top by Δscore:

Variant	Effect	Δscore
3:186615679:CCACA:C	acceptor_loss	1.0000
3:186615680:CACA:C	acceptor_loss	1.0000
3:186615681:ACAG:A	acceptor_loss	1.0000
3:186615682:C:G	acceptor_gain	1.0000
3:186615682:CAGC:C	acceptor_loss	1.0000
3:186615683:A:AG	acceptor_gain	1.0000
3:186615683:A:AT	acceptor_loss	1.0000
3:186615684:G:A	acceptor_loss	1.0000
3:186615684:G:GA	acceptor_gain	1.0000
3:186615684:GC:G	acceptor_gain	1.0000
3:186615684:GCA:G	acceptor_gain	1.0000
3:186615684:GCAGC:G	acceptor_gain	1.0000
3:186615791:AGCAT:A	donor_gain	1.0000
3:186615792:GCAT:G	donor_gain	1.0000
3:186615792:GCATG:G	donor_gain	1.0000
3:186615794:AT:A	donor_gain	1.0000
3:186615794:ATGTG:A	donor_loss	1.0000
3:186615796:G:GG	donor_gain	1.0000
3:186615796:GTGA:G	donor_loss	1.0000
3:186615797:T:A	donor_loss	1.0000
3:186615798:GAG:G	donor_loss	1.0000
3:186615799:AGT:A	donor_loss	1.0000
3:186616437:CTCCA:C	acceptor_loss	1.0000
3:186616438:TCCA:T	acceptor_loss	1.0000
3:186616439:CCA:C	acceptor_loss	1.0000
3:186616440:CA:C	acceptor_loss	1.0000
3:186616441:A:AG	acceptor_gain	1.0000
3:186616441:A:AT	acceptor_loss	1.0000
3:186616442:G:A	acceptor_loss	1.0000
3:186616442:G:GG	acceptor_gain	1.0000

AlphaMissense

2360 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:186616458:T:A	C114S	0.997
3:186616459:G:C	C114S	0.997
3:186616512:T:A	C132S	0.997
3:186616513:G:C	C132S	0.997
3:186613235:T:A	C32S	0.995
3:186613236:G:C	C32S	0.995
3:186618564:T:C	F201S	0.995
3:186619869:T:A	C230S	0.995
3:186619870:G:C	C230S	0.995
3:186615769:T:A	C100S	0.994
3:186615770:G:C	C100S	0.994
3:186616459:G:A	C114Y	0.994
3:186617337:G:C	R187P	0.994
3:186618564:T:G	F201C	0.994
3:186616512:T:C	C132R	0.993
3:186613236:G:A	C32Y	0.992
3:186613312:A:C	K57N	0.991
3:186613312:A:T	K57N	0.991
3:186616458:T:C	C114R	0.991
3:186616460:T:G	C114W	0.991
3:186615769:T:C	C100R	0.990
3:186616459:G:T	C114F	0.990
3:186613324:C:A	N61K	0.989
3:186613324:C:G	N61K	0.989
3:186613326:A:C	Q62P	0.989
3:186615780:G:C	R103S	0.989
3:186615780:G:T	R103S	0.989
3:186616513:G:A	C132Y	0.989
3:186618563:T:C	F201L	0.989
3:186618565:T:A	F201L	0.989

dbSNP variants (sampled 300 via entrez): RS1000277790 (3:186611694 C>T), RS1000521655 (3:186616075 A>C), RS1001126504 (3:186617724 C>T), RS1001171110 (3:186618073 T>C), RS1001248294 (3:186613629 G>A), RS1001796224 (3:186614714 T>C), RS1002052933 (3:186612800 A>G,T), RS1002698298 (3:186612528 A>G), RS1003303001 (3:186619080 A>T), RS1003867227 (3:186613338 T>C), RS1003972913 (3:186619662 A>G,T), RS1003974988 (3:186612453 C>A,T), RS1004026351 (3:186613359 G>A), RS1004078735 (3:186613617 C>G), RS1004151752 (3:186611373 G>A,C)

Disease associations

OMIM: gene MIM:138680 | disease phenotypes: MIM:203650, MIM:167030

GenCC curated gene-disease

Disease	Classification	Inheritance
alopecia-intellectual disability syndrome 1	Limited	Autosomal recessive

Mondo (2): alopecia-intellectual disability syndrome 1 (MONDO:0021035), nephrolithiasis, calcium oxalate (MONDO:0957318)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000613	Photophobia
HP:0000815	Hypergonadotropic hypogonadism
HP:0000962	Hyperkeratosis
HP:0001156	Brachydactyly
HP:0001171	Split hand
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001371	Flexion contracture
HP:0001510	Growth delay
HP:0001596	Alopecia
HP:0002209	Sparse scalp hair
HP:0002231	Sparse body hair
HP:0002289	Alopecia universalis
HP:0002353	EEG abnormality
HP:0002650	Scoliosis
HP:0002750	Delayed skeletal maturation
HP:0004322	Short stature
HP:0005105	Abnormal nasal morphology
HP:0008064	Ichthyosis
HP:0008070	Sparse hair
HP:0010864	Severe intellectual disability
HP:0011842	Abnormal skeletal morphology
HP:0100840	Aplasia/Hypoplasia of the eyebrow
HP:0200012	Short corpus callosum

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001574_5	Activated partial thromboplastin time	1.000000e-111
GCST006585_921	Blood protein levels	4.000000e-25

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295694 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Ozone	decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	affects expression, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
bisphenol A	affects expression	1
chlortoluron	decreases expression	1
deoxynivalenol	decreases expression	1
diisononyl phthalate	decreases expression, affects cotreatment	1
lead nitrate	decreases expression, affects cotreatment	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
butylbenzyl phthalate	decreases expression, affects cotreatment	1
cupric chloride	decreases expression	1
benazol P	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	increases expression	1
abrine	decreases expression, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	decreases phosphorylation	1
Zoledronic Acid	increases expression	1
Vorinostat	decreases expression	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Copper	affects binding	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118554	Binding	Binding affinity to AHSG in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02096965	PHASE1	COMPLETED	Use of Tolvaptan to Reduce Urinary Supersaturation: a Pilot Proof of Principle Study
NCT00381849	PHASE1/PHASE2	COMPLETED	Use of an Herbal Preparation to Prevent and Dissolve Kidney Stones
NCT06330246	Not specified	RECRUITING	O. Formigenes Colonization in Calcium Oxalate Kidney Stone Disease
NCT06331546	Not specified	RECRUITING	Gut Oxalate Absorption in Calcium Oxalate Stone Disease
NCT06989320	Not specified	RECRUITING	Endogenous Oxalate Synthesis in Idiopathic Calcium Oxalate Kidney Stone Disease