HSD17B12

Summary

HSD17B12 (hydroxysteroid 17-beta dehydrogenase 12, HGNC:18646) is a protein-coding gene on chromosome 11p11.2, encoding Very-long-chain 3-oxoacyl-CoA reductase (Q53GQ0). Catalyzes the second of the four reactions of the long-chain fatty acids elongation cycle. It is a selective cancer dependency (DepMap: 46.8% of cell lines).

This gene encodes a very important 17beta-hydroxysteroid dehydrogenase (17beta-HSD) that converts estrone into estradiol in ovarian tissue. This enzyme is also involved in fatty acid elongation.

Source: NCBI Gene 51144 — RefSeq curated summary.

At a glance

• GWAS associations: 27
• Clinical variants (ClinVar): 68 total — 2 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 46.8% of screened cell lines
• MANE Select transcript: NM_016142

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18646
Approved symbol	HSD17B12
Name	hydroxysteroid 17-beta dehydrogenase 12
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	KAR, SDR12C1
Ensembl gene	ENSG00000149084
Ensembl biotype	protein_coding
OMIM	609574
Entrez	51144

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 16 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000278353, ENST00000395700, ENST00000525736, ENST00000527213, ENST00000527433, ENST00000531185, ENST00000532178, ENST00000533090, ENST00000533802, ENST00000534053, ENST00000636007, ENST00000636722, ENST00000637401, ENST00000638034, ENST00000865203, ENST00000865204, ENST00000865205, ENST00000865206, ENST00000865207, ENST00000865208, ENST00000925444, ENST00000925445, ENST00000925446, ENST00000925447, ENST00000966177

RefSeq mRNA: 1 — MANE Select: NM_016142 NM_016142

CCDS: CCDS7905

Canonical transcript exons

ENST00000278353 — 11 exons

Exon	Start	End
ENSE00001182848	43855144	43856615
ENSE00003507771	43798320	43798427
ENSE00003515146	43816347	43816391
ENSE00003526257	43754046	43754121
ENSE00003545314	43750911	43750957
ENSE00003565004	43830976	43831010
ENSE00003612894	43838317	43838398
ENSE00003635957	43815437	43815501
ENSE00003644889	43839999	43840064
ENSE00003685422	43854715	43854864
ENSE00003798791	43680738	43680987

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 84.5122 / max 855.1300, expressed in 1820 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113958	44.7312	1816
113960	27.4558	1808
113959	11.6076	1722
113957	0.7176	420

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.07	gold quality
pigmented layer of retina	UBERON:0001782	98.68	gold quality
retina	UBERON:0000966	98.66	gold quality
pancreatic ductal cell	CL:0002079	98.63	gold quality
cranial nerve II	UBERON:0000941	98.42	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.38	gold quality
inferior vagus X ganglion	UBERON:0005363	98.37	gold quality
cardia of stomach	UBERON:0001162	98.30	gold quality
renal medulla	UBERON:0000362	98.26	gold quality
adrenal tissue	UBERON:0018303	98.26	gold quality
dorsal root ganglion	UBERON:0000044	98.19	gold quality
epithelial cell of pancreas	CL:0000083	98.13	gold quality
substantia nigra pars compacta	UBERON:0001965	98.13	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.03	gold quality
colonic mucosa	UBERON:0000317	97.96	gold quality
pons	UBERON:0000988	97.89	gold quality
pylorus	UBERON:0001166	97.89	gold quality
pericardium	UBERON:0002407	97.89	gold quality
olfactory bulb	UBERON:0002264	97.88	gold quality
seminal vesicle	UBERON:0000998	97.77	gold quality
mammary duct	UBERON:0001765	97.77	gold quality
cartilage tissue	UBERON:0002418	97.77	gold quality
choroid plexus epithelium	UBERON:0003911	97.77	gold quality
islet of Langerhans	UBERON:0000006	97.72	gold quality
superior vestibular nucleus	UBERON:0007227	97.67	gold quality
buccal mucosa cell	CL:0002336	97.58	gold quality
epithelium of mammary gland	UBERON:0003244	97.56	gold quality
ventral tegmental area	UBERON:0002691	97.55	gold quality
trigeminal ganglion	UBERON:0001675	97.51	gold quality
subthalamic nucleus	UBERON:0001906	97.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.09
E-CURD-135	no	881.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting HSD17B12, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
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-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4729	99.69	72.18	4233

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 46.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• 17beta-HSD12 is the major estrogenic 17beta-HSD responsible for the conversion of E1 to E2 in women. (PMID:16166196)
• Location of 17beta-hydroxysteroid dehydrogenase type 12 through the human body. (PMID:16621523)
• 17beta-HSD12 is not \related to intratumoral estradiol biosynthesis in human breast carcinoma, but is correlated with production of very long chain fatty acids and tumor progresssion. (PMID:19190350)
• determined the activity and expression levels of known estrogenic 17beta-HSDs, namely types 1, 7 and 12 17beta-HSD in preadipocytes before and after differentiation into mature adipocytes (PMID:19429442)
• There is no difference in catalytic properties between variants of 17beta-HSD types 7 and 12 and wild-type enzymes, while variants p.Glu77Gly and p.Lys183Arg in 17beta-HSD type 5 showed a slightly decreased activity. (PMID:19460435)
• SREBP-1 represents one of the transcriptional regulators of human 17beta-HSD12. (PMID:19533843)
• High HSD17B12 expression is associated with neoplasms. (PMID:21409596)
• HSD17B12 overexpression is shown to be a marker of poor survival in patients with ovarian cancer; expression in the tumor and function of this enzyme facilitates ovarian cancer progression. (PMID:22903146)
• These evidences were suggestive of a 46,XY DSD due to 17betaHSD3 deficiency. An homozygous mutation (IVS3 -1 G>C or c.326-1G>C) of the 17betaHSD3 gene was discovered. (PMID:23435447)
• Significant associations have been found between CpG sites and patient sex, including DNA methylation in CASP6, a gene that may respond to estradiol treatment, and in HSD17B12, which encodes a sex steroid hormone. (PMID:24058506)
• The expression of HSD17B12 increased along with the severity of ovarian cancer, and the expression mimicked COX-2 expression and intensity. This further suggests the involvement of HSD17B12 in AA production, and its coexpression with COX-2 indicates a role for the enzyme in the increased prostaglandin production during ovarian cancer progression. (PMID:29324448)
• Among lung-expressing enzymes only HSD17beta12 exhibited activity against tobacco-specific carcinogen nitrosamine NNK. siRNA knock-down of HSD17beta12 resulted in significant decreases in (R)-NNAL-formation activity in HEK293 cells. These data suggest that both cytosolic and microsomal enzymes are active against NNK and that HSD17beta12 is the major active microsomal reductase that contributes to (R)-NNAL formation in … (PMID:29788210)
• Study identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted cutaneous melanoma disease-specific survival. The ELOVL2 rs3734398 variant CC genotype was found to be associated with a significantly increased mRNA expression level. (PMID:30734280)
• Silencing of hydroxysteroid 17-beta dehydrogenase 12 essentially catalyzes the 3-ketoacyl-CoA reduction step in long-chain fatty acids production, modulates proliferation and migration of breast cancer cells in a cell line-dependent manner. (PMID:31302749)
• Very-long-chain fatty acid metabolic capacity of 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) promotes replication of hepatitis C virus and related flaviviruses. (PMID:32132633)
• An Integrative Phenotype-Genotype Approach Using Phenotypic Characteristics from the UAE National Diabetes Study Identifies HSD17B12 as a Candidate Gene for Obesity and Type 2 Diabetes. (PMID:32340285)
• Functional genetic variant of HSD17B12 in the fatty acid biosynthesis pathway predicts the outcome of colorectal cancer. (PMID:33118286)
• Association of genetic polymorphisms with local steroid metabolism in human benign breasts. (PMID:34762930)
• Genetic variants in CYP2B6 and HSD17B12 associated with risk of squamous cell carcinoma of the head and neck. (PMID:35404482)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hsd17b12a	ENSDARG00000015709
danio_rerio	hsd17b12b	ENSDARG00000035872
mus_musculus	Hsd17b12	ENSMUSG00000027195
rattus_norvegicus	Hsd17b12	ENSRNOG00000009630

Paralogs (25): HSD17B6 (ENSG00000025423), RDH11 (ENSG00000072042), HSD17B10 (ENSG00000072506), DHRS9 (ENSG00000073737), HSD17B2 (ENSG00000086696), HSD17B14 (ENSG00000087076), DHRS12 (ENSG00000102796), HSDL1 (ENSG00000103160), HSD17B1 (ENSG00000108786), RDH10 (ENSG00000121039), HSD17B3 (ENSG00000130948), HSD17B7 (ENSG00000132196), HSD17B4 (ENSG00000133835), RDH5 (ENSG00000135437), RDH16 (ENSG00000139547), RDH12 (ENSG00000139988), BDH1 (ENSG00000161267), DHRS3 (ENSG00000162496), SDR9C7 (ENSG00000170426), HSD17B13 (ENSG00000170509), SDR16C5 (ENSG00000170786), HSD11B2 (ENSG00000176387), WWOX (ENSG00000186153), HSD17B11 (ENSG00000198189), HSD17B8 (ENSG00000204228)

Protein

Protein identifiers

Very-long-chain 3-oxoacyl-CoA reductase — Q53GQ0 (reviewed: Q53GQ0)

Alternative names: 17-beta-hydroxysteroid dehydrogenase 12, 3-ketoacyl-CoA reductase, Estradiol 17-beta-dehydrogenase 12, Short chain dehydrogenase/reductase family 12C member 1

All UniProt accessions (7): Q53GQ0, A0A1B0GU83, A0A1B0GV93, A0A1B0GVY6, A0A1B0GW27, A0A1B0GW85, E9PI21

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the second of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme has a 3-ketoacyl-CoA reductase activity, reducing 3-ketoacyl-CoA to 3-hydroxyacyl-CoA, within each cycle of fatty acid elongation. Thereby, it may participate in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May also catalyze the transformation of estrone (E1) into estradiol (E2) and play a role in estrogen formation.

Subunit / interactions. Interacts with ELOVL1 and LASS2.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in most tissues tested. Highly expressed in the ovary and mammary. Expressed in platelets.

Domain organisation. The di-lysine motif confers endoplasmic reticulum localization for type I membrane proteins.

Pathway. Lipid metabolism; fatty acid biosynthesis. Steroid biosynthesis; estrogen biosynthesis.

Similarity. Belongs to the short-chain dehydrogenases/reductases (SDR) family. 17-beta-HSD 3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q53GQ0-1	1	yes
Q53GQ0-2	2

RefSeq proteins (1): NP_057226* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002347	SDR_fam	Family
IPR020904	Sc_DH/Rdtase_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR051019	VLCFA-Steroid_DH	Family

Pfam: PF00106

Enzyme classification (BRENDA):

• EC 1.1.1.62 — 17beta-estradiol 17-dehydrogenase (BRENDA: 20 organisms, 283 substrates, 790 inhibitors, 95 Km, 44 kcat entries)

Substrate kinetics (BRENDA)

32 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ESTRADIOL-17BETA	0.0008–0.025	14
ESTRONE	—	10
NADP+	0.0001–9	9
17BETA-ESTRADIOL	0.0006–0.082	7
NADPH	0.0003–0.16	7
ESTRADIOL	0.0036–0.118	6
TESTOSTERONE	0.0071–0.263	4
DEHYDROEPIANDROSTERONE	0.0172–0.0598	3
5-ANDROSTENE-3BETA,17BETA-DIOL	0.0066–0.0078	2
5ALPHA-DIHYDROTESTOSTERONE	0.0067–0.118	2
5BETA-PREGNAN-20ALPHA-OL-3-ONE	0.0011–0.0033	2
DIHYDROTESTOSTERONE	0.0043–0.033	2
NAD+	0.357–0.5	2
(S)-INDAN-1-OL	0.508	1
1-METHYL-6-DEHYDROESTRADIOL	0.0085	1

Catalyzed reactions (Rhea), 7 shown:

• 17beta-estradiol + NAD(+) = estrone + NADH + H(+) (RHEA:24612)
• 17beta-estradiol + NADP(+) = estrone + NADPH + H(+) (RHEA:24616)
• 3-oxooctadecanoyl-CoA + NADPH + H(+) = (3R)-hydroxyoctadecanoyl-CoA + NADP(+) (RHEA:39151)
• 3-oxo-(8Z,11Z,14Z)-eicosatrienoyl-CoA + NADPH + H(+) = (3R)-hydroxy-(8Z,11Z,14Z)-eicosatrienoyl-CoA + NADP(+) (RHEA:39311)
• (7Z,10Z,13Z,16Z)-3-oxodocosatetraenoyl-CoA + NADPH + H(+) = (3R)-hydroxy-(7Z,10Z,13Z,16Z)-docosatetraenoyl-CoA + NADP(+) (RHEA:39323)
• 3-oxo-(7Z,10Z,13Z,16Z,19Z)-docosapentaenoyl-CoA + NADPH + H(+) = (3R)-hydroxy-(7Z,10Z,13Z,16Z,19Z)-docosapentaenoyl-CoA + NADP(+) (RHEA:39459)
• a very-long-chain (3R)-3-hydroxyacyl-CoA + NADP(+) = a very-long-chain 3-oxoacyl-CoA + NADPH + H(+) (RHEA:48680)

UniProt features (13 total): transmembrane region 3, mutagenesis site 2, binding site 2, splice variant 2, chain 1, sequence variant 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53GQ0-F1	94.55	0.88

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): 202 (proton acceptor)

Ligand- & substrate-binding residues (2): 50–79; 189

Mutagenesis-validated functional residues (2):

Position	Phenotype
196	no effect.
234	allows the conversion of androstenedione to testosterone.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-193048	Androgen biosynthesis
R-HSA-75876	Synthesis of very long-chain fatty acyl-CoAs

MSigDB gene sets: 273 (showing top): REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_BIOSYNTHESIS_OF_UNSATURATED_FATTY_ACIDS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOMF_STEROID_DEHYDROGENASE_ACTIVITY_ACTING_ON_THE_CH_OH_GROUP_OF_DONORS_NAD_OR_NADP_AS_ACCEPTOR, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACYL_COA_METABOLIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP

GO Biological Process (8): estrogen biosynthetic process (GO:0006703), positive regulation of cell-substrate adhesion (GO:0010811), fatty acid elongation, saturated fatty acid (GO:0019367), extracellular matrix organization (GO:0030198), long-chain fatty-acyl-CoA biosynthetic process (GO:0035338), lipid metabolic process (GO:0006629), fatty acid biosynthetic process (GO:0006633), steroid biosynthetic process (GO:0006694)

GO Molecular Function (7): fibronectin binding (GO:0001968), estradiol 17-beta-dehydrogenase [NAD(P)+] activity (GO:0004303), collagen binding (GO:0005518), heparin binding (GO:0008201), oxidoreductase activity (GO:0016491), very-long-chain 3-oxoacyl-CoA reductase activity (GO:0141040), protein binding (GO:0005515)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), fatty acid elongase complex (GO:0009923), extracellular matrix (GO:0031012), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of steroid hormones	1
Fatty acyl-CoA biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid biosynthetic process	2
estrogen metabolic process	1
hormone biosynthetic process	1
steroid hormone biosynthetic process	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
positive regulation of cell adhesion	1
fatty acid elongation	1
extracellular structure organization	1
external encapsulating structure organization	1
long-chain fatty-acyl-CoA metabolic process	1
fatty-acyl-CoA biosynthetic process	1
primary metabolic process	1
fatty acid metabolic process	1
monocarboxylic acid biosynthetic process	1
steroid metabolic process	1
protein binding	1
steroid dehydrogenase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
protein-containing complex binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
catalytic activity	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
binding	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
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2454 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSD17B12	TECR	Q9NZ01	902
HSD17B12	COASY	Q13057	865
HSD17B12	HSD17B7	P56937	727
HSD17B12	DUSP12	Q9UNI6	675
HSD17B12	HACD2	Q6Y1H2	650
HSD17B12	HACD1	B0YJ81	638
HSD17B12	HSD17B1	P14061	633
HSD17B12	HACD3	Q9P035	626
HSD17B12	LMO1	P25800	622
HSD17B12	IL31RA	Q8NI17	621
HSD17B12	ELOVL1	Q9BW60	605
HSD17B12	HACD4	Q5VWC8	600
HSD17B12	DDX4	Q9NQI0	581
HSD17B12	HSD17B8	Q92506	565
HSD17B12	ELOVL5	Q9NYP7	540

IntAct

176 interactions, top by confidence:

A	B	Type	Score
UBQLN1	HSD17B12	psi-mi:“MI:0915”(physical association)	0.720
HSD17B12	UBQLN1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TECR	HACD1	psi-mi:“MI:0914”(association)	0.700
HSD17B12	FGFR3	psi-mi:“MI:0915”(physical association)	0.660
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
	DDX3X	psi-mi:“MI:0914”(association)	0.630
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
UBQLN1	HSD17B12	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (307): HSD17B12 (Two-hybrid), HSD17B12 (Affinity Capture-MS), HSD17B12 (Affinity Capture-MS), AFG3L2 (Co-fractionation), ATP1A1 (Co-fractionation), ATP5C1 (Co-fractionation), COPB1 (Co-fractionation), ETFA (Co-fractionation), FASN (Co-fractionation), HSD17B12 (Co-fractionation), HSD17B12 (Co-fractionation), HSD17B12 (Co-fractionation), HSD17B12 (Co-fractionation), HSD17B12 (Co-fractionation), HSD17B12 (Co-fractionation)

ESM2 similar proteins: A0A017SE81, A1C6J8, A1DH66, A2QCH3, A3LXZ3, A4QTE3, A5DND6, A5E0R1, A6RBW9, A6SG70, A6ZLA1, A7F8T1, A7TMJ2, A8N6B4, A8Q1U2, B0D8R3, B0XSI3, B2B3L4, B2WMJ3, B3LN00, G4N286, G9N4A9, P0CR34, P0CR35, P0CR36, P0CR37, P38286, Q09517, Q0CY11, Q0U3N7, Q0WRJ2, Q10245, Q1DNC5, Q2H1V7, Q2UET3, Q4P622, Q4X117, Q53GQ0, Q59V93, Q5B0R9

Diamond homologs: A0A1U8QWA2, A1C6J8, A1DH66, A2QCH3, A3LXZ3, A4QTE3, A5DND6, A5E0R1, A5PJF6, A6RBW9, A6SG70, A6ZLA1, A7F8T1, A7IQF2, A7TMJ2, A8N6B4, A8Q1U2, B0D8R3, B0XSI3, B2B3L4, B2WMJ3, B3LN00, G0RNA2, O16925, O17795, O31767, O54939, O57314, O70503, P0CR34, P0CR35, P14802, P37058, P38286, P41177, P51831, P70385, Q09517, Q0CY11, Q0IH28

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 167 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
Signaling by ALK	5	23.8×	7e-04
Dengue Virus Attachment and Entry	6	13.0×	8e-04
Constitutive Signaling by Aberrant PI3K in Cancer	8	8.5×	7e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	6.5×	3e-03
Signaling by Interleukins	11	5.9×	7e-04
Signaling by Receptor Tyrosine Kinases	12	5.2×	7e-04
RAF/MAP kinase cascade	10	5.1×	3e-03
PIP3 activates AKT signaling	9	5.0×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	7	20.8×	2e-05
vascular endothelial growth factor receptor signaling pathway	5	16.9×	2e-03
cell surface receptor protein tyrosine kinase signaling pathway	13	15.9×	2e-09
autophagosome assembly	7	11.1×	7e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	15	8.3×	3e-07
protein autophosphorylation	8	8.2×	1e-03
negative regulation of neuron apoptotic process	8	6.2×	6e-03
cell migration	13	5.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	46
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1703555	GRCh37/hg19 11p11.2(chr11:43769957-44952669)	Pathogenic
1707422	GRCh37/hg19 11p11.2-q12.2(chr11:51581311-54891247)x3	Pathogenic

SpliceAI

2294 predictions. Top by Δscore:

Variant	Effect	Δscore
11:43722383:G:GT	donor_gain	1.0000
11:43750907:CCA:C	acceptor_loss	1.0000
11:43750908:CA:C	acceptor_loss	1.0000
11:43750909:A:AG	acceptor_gain	1.0000
11:43750909:A:T	acceptor_loss	1.0000
11:43750909:AGTT:A	acceptor_gain	1.0000
11:43750910:G:GT	acceptor_gain	1.0000
11:43750910:GT:G	acceptor_gain	1.0000
11:43750910:GTT:G	acceptor_gain	1.0000
11:43750910:GTTG:G	acceptor_gain	1.0000
11:43750955:GAG:G	donor_gain	1.0000
11:43750958:G:GC	donor_loss	1.0000
11:43798302:T:TA	acceptor_gain	1.0000
11:43798314:CCCTA:C	acceptor_loss	1.0000
11:43798315:CCTA:C	acceptor_loss	1.0000
11:43798316:CTA:C	acceptor_loss	1.0000
11:43798317:TA:T	acceptor_loss	1.0000
11:43798318:A:AG	acceptor_gain	1.0000
11:43798318:AGA:A	acceptor_loss	1.0000
11:43798319:G:GT	acceptor_gain	1.0000
11:43798319:GA:G	acceptor_gain	1.0000
11:43798319:GAA:G	acceptor_gain	1.0000
11:43798319:GAAGA:G	acceptor_gain	1.0000
11:43798426:AGG:A	donor_loss	1.0000
11:43798427:GGTT:G	donor_loss	1.0000
11:43798428:G:A	donor_loss	1.0000
11:43798428:G:GG	donor_gain	1.0000
11:43798429:T:G	donor_loss	1.0000
11:43815430:A:AG	acceptor_gain	1.0000
11:43815432:TTCA:T	acceptor_loss	1.0000

AlphaMissense

2023 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:43815441:C:A	N132K	0.998
11:43815441:C:G	N132K	0.998
11:43838338:C:A	N186K	0.996
11:43838338:C:G	N186K	0.996
11:43750914:T:A	V55D	0.995
11:43680981:T:A	W52R	0.994
11:43680981:T:C	W52R	0.994
11:43754079:A:C	S81R	0.994
11:43754081:C:A	S81R	0.994
11:43754081:C:G	S81R	0.994
11:43838398:G:C	K206N	0.994
11:43838398:G:T	K206N	0.994
11:43840018:C:T	S213F	0.994
11:43840027:T:C	L216P	0.994
11:43750911:T:A	V54D	0.993
11:43750920:G:A	G57D	0.993
11:43750922:A:C	S58R	0.993
11:43750924:T:A	S58R	0.993
11:43750924:T:G	S58R	0.993
11:43750932:G:A	G61E	0.993
11:43838345:T:C	S189P	0.993
11:43854805:G:C	A259P	0.993
11:43815440:A:T	N132I	0.992
11:43830992:T:C	L173P	0.992
11:43854715:A:C	S229R	0.992
11:43854717:T:A	S229R	0.992
11:43854717:T:G	S229R	0.992
11:43854842:G:A	G271E	0.992
11:43750938:G:A	G63E	0.991
11:43840017:T:C	S213P	0.991

dbSNP variants (sampled 300 via entrez): RS1000008734 (11:43738292 G>A), RS1000012758 (11:43634653 C>G,T), RS1000022079 (11:43638309 G>A), RS1000028515 (11:43673597 A>G), RS1000046186 (11:43795525 T>A,C), RS1000055600 (11:43771602 G>A), RS1000066944 (11:43654122 G>T), RS1000083191 (11:43620105 T>C,G), RS1000088403 (11:43673842 G>C), RS1000094318 (11:43809746 G>A), RS1000117074 (11:43689858 C>T), RS1000118654 (11:43594128 G>C), RS1000129243 (11:43831667 A>G), RS1000129908 (11:43585992 A>G), RS1000131006 (11:43768428 C>T)

Disease associations

OMIM: gene MIM:609574 | disease phenotypes: MIM:601224

GenCC curated gene-disease

Mondo (1): Potocki-Shaffer syndrome (MONDO:0011022)

Orphanet (1): Potocki-Shaffer syndrome (Orphanet:52022)

HPO phenotypes

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

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST001660_4	Neuroblastoma	5.000000e-08
GCST002483_3	Lung function (forced vital capacity)	4.000000e-08
GCST002644_2	Birth length	1.000000e-06
GCST002783_269	Body mass index	3.000000e-08
GCST002783_624	Body mass index	3.000000e-08
GCST002783_69	Body mass index	4.000000e-07
GCST004510_6	Sporadic neuroblastoma	1.000000e-07
GCST004773_7	Type 2 diabetes	4.000000e-10
GCST005195_112	Coronary artery disease	1.000000e-08
GCST005830_75	Hand grip strength	6.000000e-09
GCST006802_35	Body mass index	1.000000e-06
GCST007429_143	Lung function (FVC)	4.000000e-15
GCST007432_140	FEV1	1.000000e-13
GCST007565_130	Morning person	4.000000e-14
GCST007576_24	Chronotype	4.000000e-14
GCST008129_73	Body mass index	5.000000e-14
GCST008151_84	Waist circumference	4.000000e-07
GCST008160_36	Waist circumference	4.000000e-07
GCST009379_315	Type 2 diabetes	6.000000e-13
GCST010152_7	Neuroblastoma or malignant cutaneous melanoma	4.000000e-07
GCST010242_251	HDL cholesterol levels	1.000000e-08
GCST010774_3	Essential hypertension (time to event)	7.000000e-08
GCST010866_80	Coronary artery disease	3.000000e-08
GCST010988_413	Adult body size	2.000000e-24
GCST012037_4	Sleep start time	1.000000e-08
GCST90000047_167	Age at first sexual intercourse	2.000000e-13
GCST90000050_51	Age at first birth	2.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0006784	body height at birth
EFO:0004340	body mass index
EFO:0006941	grip strength measurement
EFO:0004314	forced expiratory volume
EFO:0008328	chronotype measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004918	age at diagnosis
EFO:0009749	age at first sexual intercourse measurement
EFO:0009101	age at first birth measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538356	Potocki-Shaffer syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5998 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.27	Kd	5.394	nM	CHEMBL5653589
8.27	ED50	5.394	nM	CHEMBL5653589
7.27	Kd	53.27	nM	CHEMBL3752910
7.27	ED50	53.27	nM	CHEMBL3752910
5.16	IC50	6940	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 28 total; 3 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148543: Binding affinity to human HSD17B12 incubated for 45 mins by Kinobead based pull down assay	kd	0.0054	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148543: Binding affinity to human HSD17B12 incubated for 45 mins by Kinobead based pull down assay	kd	0.0533	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178878: Inhibition of HSD17B12 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	6.9400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	3
sodium arsenite	increases expression, increases abundance	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
cobaltous chloride	increases expression	1
CGP 52608	affects binding, increases reaction	1
epoxiconazole	increases expression	1
bisphenol B	increases expression	1
ramelteon	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic	increases abundance, increases expression	1
Benztropine	increases expression	1
Clozapine	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases chemical synthesis	1
Estrone	increases metabolic processing	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Furaldehyde	affects cotreatment, decreases expression	1
Isoniazid	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
NADP	affects binding, increases activity	1
Phenobarbital	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3111003	Binding	Inhibition of 17-beta HSD12 (unknown origin) transfected in HEK293 cells using [14C]E1 as substrate at 10 uM	Discovery of a non-estrogenic irreversible inhibitor of 17β-hydroxysteroid dehydrogenase type 1 from 3-substituted-16β-(m-carbamoylbenzyl)-estradiol derivatives. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XP62	HAP1 HSD17B12 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford