HHAT

Summary

HHAT (hedgehog acyltransferase, HGNC:18270) is a protein-coding gene on chromosome 1q32.2, encoding Protein-cysteine N-palmitoyltransferase HHAT (Q5VTY9). Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling.

‘Skinny hedgehog’ (SKI1) encodes an enzyme that acts within the secretory pathway to catalyze amino-terminal palmitoylation of ‘hedgehog’ (see MIM 600725).

Source: NCBI Gene 55733 — RefSeq curated summary.

At a glance

• Gene–disease (curated): chondrodysplasia-pseudohermaphroditism syndrome (Strong, GenCC)
• GWAS associations: 17
• Clinical variants (ClinVar): 191 total — 7 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes
• MANE Select transcript: NM_018194

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18270
Approved symbol	HHAT
Name	hedgehog acyltransferase
Location	1q32.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10724, MART-2, MART2, Skn, ski, rasp, sit, GUP2
Ensembl gene	ENSG00000054392
Ensembl biotype	protein_coding
OMIM	605743
Entrez	55733

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000261458, ENST00000367009, ENST00000367010, ENST00000413764, ENST00000426968, ENST00000537898, ENST00000541565, ENST00000545154, ENST00000545781, ENST00000857145, ENST00000857146, ENST00000857147, ENST00000857148, ENST00000857149, ENST00000969947, ENST00000969948

RefSeq mRNA: 6 — MANE Select: NM_018194 NM_001122834, NM_001170564, NM_001170580, NM_001170587, NM_001170588, NM_018194

CCDS: CCDS1495, CCDS53471, CCDS53472, CCDS53473

Canonical transcript exons

ENST00000261458 — 12 exons

Exon	Start	End
ENSE00000841378	210404464	210404679
ENSE00000841379	210418154	210418325
ENSE00001183003	210623526	210623670
ENSE00001183016	210400468	210400662
ENSE00001234562	210587898	210588099
ENSE00001911926	210328902	210329104
ENSE00003476299	210348933	210349066
ENSE00003493957	210387468	210387581
ENSE00003657049	210362852	210362919
ENSE00003729271	210513153	210513188
ENSE00003784233	210464505	210464655
ENSE00003842999	210674288	210676290

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 82.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.0580 / max 37.6472, expressed in 1315 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8388	1.4907	852
8387	0.5170	260
8389	0.4008	192
8390	0.1690	48
8393	0.1640	81
201940	0.1539	57
201941	0.1300	53
8392	0.0325	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.04	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.04	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.73	gold quality
right adrenal gland cortex	UBERON:0035827	79.45	gold quality
right adrenal gland	UBERON:0001233	78.45	gold quality
left adrenal gland	UBERON:0001234	77.62	gold quality
stromal cell of endometrium	CL:0002255	77.41	gold quality
left adrenal gland cortex	UBERON:0035825	77.17	gold quality
right uterine tube	UBERON:0001302	77.13	gold quality
adrenal gland	UBERON:0002369	76.10	gold quality
endometrium	UBERON:0001295	75.85	gold quality
gall bladder	UBERON:0002110	74.68	gold quality
islet of Langerhans	UBERON:0000006	73.71	gold quality
thyroid gland	UBERON:0002046	72.51	gold quality
ventricular zone	UBERON:0003053	72.39	gold quality
saliva-secreting gland	UBERON:0001044	72.36	gold quality
minor salivary gland	UBERON:0001830	72.11	gold quality
left lobe of thyroid gland	UBERON:0001120	72.10	gold quality
fallopian tube	UBERON:0003889	71.54	gold quality
endocervix	UBERON:0000458	71.13	gold quality
placenta	UBERON:0001987	71.05	gold quality
prostate gland	UBERON:0002367	70.96	gold quality
kidney	UBERON:0002113	70.88	gold quality
smooth muscle tissue	UBERON:0001135	70.74	gold quality
cortex of kidney	UBERON:0001225	70.68	gold quality
adult mammalian kidney	UBERON:0000082	70.60	gold quality
prefrontal cortex	UBERON:0000451	70.37	gold quality
right lobe of thyroid gland	UBERON:0001119	70.21	gold quality
uterine cervix	UBERON:0000002	70.16	gold quality
skin of abdomen	UBERON:0001416	70.09	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KMT2B, SOX2

miRNA regulators (miRDB)

81 targeting HHAT, 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-7110-3P	100.00	73.18	2486
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577

Literature-anchored findings (GeneRIF, showing 17)

• SKI-1/S1P activity is thus essential for hepatitis C virus production and its inhibition should be considered for antiviral drug development. (PMID:22626636)
• SKN is necessary for the proliferation of the non-small cell lung carcinoma cells (PMID:22733134)
• These findings define residues and regions within Shh that are necessary for its recognition as a substrate for Hhat-mediated palmitoylation. (PMID:23112049)
• rs7527939 is the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus. (PMID:23142968)
• provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development (PMID:24784881)
• analysis of hedgehog acyltransferase membrane topology (PMID:25488661)
• three distinct members [porcupine (PORCN), hedgehog (Hh) acyltransferase (HHAT) and ghrelin O-acyltransferase (GOAT)] have been shown to acylate specific proteins or peptides. (PMID:25849925)
• Hhat plays a critical role in ER positive, HER2 amplified, and hormone resistant breast cancer proliferation. (PMID:25889650)
• Data suggest that substrate specificity of hedgehog acyltransferase (HHAT) in palmitoylation reaction extends to oligopeptide fragments of Sonic hedgehog protein (SHH). (PMID:26334609)
• we confirm that biallelic loss of function HHAT variant ( likely deleterious) cause microcephaly, skeletal dysplasia and cerebellar vermis hypoplasia. (PMID:30912300)
• HHAT is regulated in SSc in a TGFbeta-dependent manner and in turn stimulates TGFbeta-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling. (PMID:31177096)
• Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome. (PMID:33749989)
• Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. (PMID:34112694)
• Structure, mechanism, and inhibition of Hedgehog acyltransferase. (PMID:34890564)
• A Homozygous Missense Variant in Hedgehog Acyltransferase (HHAT) Gene Associated with 46,XY Gonadal Dysgenesis. (PMID:35045414)
• Hedgehog acyltransferase catalyzes a random sequential reaction and utilizes multiple fatty acyl-CoA substrates. (PMID:36030053)
• Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development. (PMID:36631813)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hhat	ENSDARG00000074428
mus_musculus	Hhat	ENSMUSG00000037375
rattus_norvegicus	Hhat	ENSRNOG00000003925
drosophila_melanogaster	rasp	FBGN0024194
caenorhabditis_elegans		WBGENE00013312
caenorhabditis_elegans		WBGENE00013852

Paralogs (1): HHATL (ENSG00000010282)

Protein

Protein identifiers

Protein-cysteine N-palmitoyltransferase HHAT — Q5VTY9 (reviewed: Q5VTY9)

Alternative names: Hedgehog acyltransferase, Melanoma antigen recognized by T-cells 2, Skinny hedgehog protein 1

All UniProt accessions (4): A0A075B6R5, B1AK61, Q5VTY9, F5H2Y1

UniProt curated annotations — full annotation on UniProt →

Function. Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling. It also catalyzes N-terminal palmitoylation of DHH. Promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where SHH palmitoylation occurs. It is an essential factor for proper embryonic development and testicular organogenesis.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Tissue specificity. Widely expressed. Expressed in fetal ovary and testis, with high levels of expression observed in Sertoli cells.

Disease relevance. Nivelon-Nivelon-Mabille syndrome (NNMS) [MIM:600092] An autosomal recessive syndrome characterized by progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Additional variable features include early infantile-onset seizures, intrauterine and postnatal growth retardation, generalized chondrodysplasia, and micromelia. 46,XY gonadal dysgenesis may be present. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by NaCl concentrations above 150 mM.

Similarity. Belongs to the membrane-bound acyltransferase family. HHAT subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
Q5VTY9-1	1	yes
Q5VTY9-2	2
Q5VTY9-3	3
Q5VTY9-4	4
Q5VTY9-5	5
Q5VTY9-6	6
Q5VTY9-7	7

RefSeq proteins (6): NP_001116306, NP_001164035, NP_001164051, NP_001164058, NP_001164059, NP_060664* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004299	MBOAT_fam	Family
IPR051085	MB_O-acyltransferase	Family

Pfam: PF03062

Catalyzed reactions (Rhea), 2 shown:

• N-terminal L-cysteinyl-[protein] + hexadecanoyl-CoA = N-terminal N-hexadecanoyl-L-cysteinyl-[protein] + CoA + H(+) (RHEA:59528)
• N-terminal L-cysteinyl-[protein]-C-terminal glycyl cholesterol ester + hexadecanoyl-CoA = N-terminal N-hexadecanoyl-L-cysteinyl-[protein]-C-terminal glycyl cholesterol ester + CoA + H(+) (RHEA:59580)

UniProt features (88 total): helix 27, topological domain 13, transmembrane region 10, splice variant 7, sequence variant 7, turn 5, lipid moiety-binding region 4, strand 4, sequence conflict 3, intramembrane region 2, mutagenesis site 2, chain 1, region of interest 1, active site 1, binding site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
6UJO	X-RAY DIFFRACTION	2.25
6UJQ	X-RAY DIFFRACTION	2.55
6UK4	X-RAY DIFFRACTION	2.7
7MHY	ELECTRON MICROSCOPY	2.7
7Q1U	ELECTRON MICROSCOPY	2.7
7URF	ELECTRON MICROSCOPY	2.8
6P64	X-RAY DIFFRACTION	3.05
6UK2	X-RAY DIFFRACTION	3.14
7MHZ	ELECTRON MICROSCOPY	3.2
7Q6Z	ELECTRON MICROSCOPY	3.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VTY9-F1	93.07	0.86

Antibody-complex structures (SAbDab): 5 — 7MHY, 7MHZ, 7Q1U, 7Q6Z, 7URF

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): 379

Ligand- & substrate-binding residues (1): 448–455

Post-translational modifications (4): 188, 242, 324, 410

Mutagenesis-validated functional residues (2):

Position	Phenotype
351	no significant effect on catalytic activity. defective hhat-mediated palmitoyl-coa uptake into microsomal membranes.
379	reduced catalytic activity. defective hhat-mediated palmitoyl-coa uptake into microsomal membranes.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5658034	HHAT G278V doesn’t palmitoylate Hh-Np

MSigDB gene sets: 907 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX

GO Biological Process (2): smoothened signaling pathway (GO:0007224), N-terminal peptidyl-L-cysteine N-palmitoylation (GO:0018009)

GO Molecular Function (7): GTP binding (GO:0005525), obsolete O-acyltransferase activity (GO:0008374), palmitoyltransferase activity (GO:0016409), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (5): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Hedgehog	1
Hh mutants abrogate ligand secretion	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cell surface receptor signaling pathway	1
N-terminal protein palmitoylation	1
peptidyl-cysteine modification	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
transferase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

710 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HHAT	MAFF	Q9ULX9	771
HHAT	MLANA	Q16655	768
HHAT	MAFG	O15525	737
HHAT	MAFK	O60675	699
HHAT	NFE2L1	Q14494	697
HHAT	NFE2	Q16621	645
HHAT	PORCN	Q9H237	628
HHAT	KIF5B	P33176	621
HHAT	MBOAT4	Q96T53	611
HHAT	SHH	Q15465	586
HHAT	POU2F3	Q9UKI9	581
HHAT	MAF	O75444	578
HHAT	SCUBE2	Q9NQ36	557
HHAT	PTCH1	Q13635	516
HHAT	GSTM2	P28161	507

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SDCBP	HHAT	psi-mi:“MI:0915”(physical association)	0.560
SDCBP	HHAT	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): SDCBP (Two-hybrid), HHAT (Positive Genetic), HHAT (Affinity Capture-RNA)

ESM2 similar proteins: A0A1B0GVZ9, A4IFN5, A5PK40, A6NH52, A6NI61, B2LYG4, B2RZC9, B6ID01, D2HKB0, D3ZG27, P86229, Q0VDI3, Q15012, Q15546, Q17QJ2, Q1RLT2, Q2TA01, Q4R4I5, Q4R6E8, Q5H8A4, Q5R7Q1, Q5RAH0, Q5RL79, Q5U3C3, Q5VTY9, Q5ZML7, Q64232, Q6PHN7, Q6QRN8, Q719N3, Q71SV0, Q8BWB6, Q8IY49, Q8N6M3, Q8NFT2, Q8R189, Q8VD53, Q8VDI9, Q8VDR5, Q9CQC4

Diamond homologs: P53154, Q08929, Q09758, Q5AKZ2, Q5VTY9, Q7Z877, Q7Z888, Q8BMT9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HHAT	up-regulates	SHH	palmitoylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	2
Uncertain significance	101
Likely benign	44
Benign	18

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1074202	NM_018194.6(HHAT):c.1134G>A (p.Trp378Ter)	Pathogenic
4729067	NM_018194.6(HHAT):c.112C>T (p.Gln38Ter)	Pathogenic
4810202	NM_018194.6(HHAT):c.727_728dup (p.Leu244fs)	Pathogenic
4810388	NM_018194.6(HHAT):c.567G>A (p.Trp189Ter)	Pathogenic
523270	GRCh37/hg19 1q32.1-32.3(chr1:204682513-212815646)	Pathogenic
987946	NM_018194.6(HHAT):c.860G>T (p.Gly287Val)	Pathogenic
987947	NM_018194.6(HHAT):c.770T>C (p.Leu257Pro)	Pathogenic
3731614	NM_018194.6(HHAT):c.218G>A (p.Trp73Ter)	Likely pathogenic
521737	NM_018194.6(HHAT):c.1A>T (p.Met1Leu)	Likely pathogenic

SpliceAI

4599 predictions. Top by Δscore:

Variant	Effect	Δscore
1:210348931:A:AG	acceptor_gain	1.0000
1:210348932:G:GG	acceptor_gain	1.0000
1:210362845:T:TA	acceptor_gain	1.0000
1:210387577:GAAAG:G	donor_gain	1.0000
1:210387578:AAAGG:A	donor_loss	1.0000
1:210387579:AAGGT:A	donor_loss	1.0000
1:210387580:AGGT:A	donor_loss	1.0000
1:210387581:GGTAT:G	donor_loss	1.0000
1:210387582:G:GA	donor_loss	1.0000
1:210387583:T:A	donor_loss	1.0000
1:210404677:CAGGT:C	donor_loss	1.0000
1:210404678:AG:A	donor_loss	1.0000
1:210404679:GGT:G	donor_loss	1.0000
1:210404680:GTAG:G	donor_loss	1.0000
1:210404681:T:A	donor_loss	1.0000
1:210464616:GCTGC:G	donor_gain	1.0000
1:210587894:CTA:C	acceptor_loss	1.0000
1:210587895:TA:T	acceptor_loss	1.0000
1:210587896:AGGT:A	acceptor_loss	1.0000
1:210587897:G:GA	acceptor_loss	1.0000
1:210587897:GGTAT:G	acceptor_gain	1.0000
1:210588095:GTCTG:G	donor_gain	1.0000
1:210588097:CTGG:C	donor_loss	1.0000
1:210588098:TGGTG:T	donor_loss	1.0000
1:210588099:GGT:G	donor_loss	1.0000
1:210588100:G:GG	donor_gain	1.0000
1:210588100:GTGA:G	donor_loss	1.0000
1:210588101:T:G	donor_loss	1.0000
1:210635908:GC:G	donor_gain	1.0000
1:210368252:GGCT:G	donor_gain	0.9900

AlphaMissense

3186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:210464651:T:A	W335R	0.998
1:210464651:T:C	W335R	0.998
1:210464653:G:C	W335C	0.998
1:210464653:G:T	W335C	0.998
1:210513157:T:C	F338L	0.998
1:210513159:T:A	F338L	0.998
1:210513159:T:G	F338L	0.998
1:210587968:T:C	F372L	0.998
1:210587970:T:A	F372L	0.998
1:210587970:T:G	F372L	0.998
1:210513161:A:T	D339V	0.997
1:210587989:C:G	H379D	0.997
1:210404539:A:C	S182R	0.996
1:210404541:C:A	S182R	0.996
1:210404541:C:G	S182R	0.996
1:210464558:T:C	F304L	0.996
1:210464560:T:A	F304L	0.996
1:210464560:T:G	F304L	0.996
1:210464624:A:C	S326R	0.996
1:210464626:C:A	S326R	0.996
1:210464626:C:G	S326R	0.996
1:210513162:T:A	D339E	0.996
1:210513162:T:G	D339E	0.996
1:210513170:T:C	L342P	0.996
1:210588016:T:A	W388R	0.996
1:210588016:T:C	W388R	0.996
1:210513161:A:C	D339A	0.995
1:210588030:C:A	N392K	0.995
1:210588030:C:G	N392K	0.995
1:210387486:T:A	W60R	0.994

dbSNP variants (sampled 300 via entrez): RS1000005042 (1:210532532 A>G), RS1000005379 (1:210417756 A>C), RS1000005654 (1:210657077 T>C), RS1000013186 (1:210411754 A>G), RS1000037981 (1:210417594 A>G), RS1000045354 (1:210574889 G>A,C), RS1000048181 (1:210618710 A>G), RS1000062753 (1:210527192 C>A), RS1000066438 (1:210646198 T>C), RS1000071905 (1:210531281 A>G), RS1000089476 (1:210580525 G>T), RS1000108565 (1:210450656 C>A,T), RS1000110826 (1:210549828 C>G,T), RS1000114686 (1:210463843 T>A,C), RS1000123315 (1:210603040 G>C)

Disease associations

OMIM: gene MIM:605743 | disease phenotypes: MIM:600092

GenCC curated gene-disease

Disease	Classification	Inheritance
chondrodysplasia-pseudohermaphroditism syndrome	Strong	Autosomal recessive

Mondo (2): chondrodysplasia-pseudohermaphroditism syndrome (MONDO:0010814), intellectual disability (MONDO:0001071)

Orphanet (2): Chondrodysplasia-difference of sex development syndrome (Orphanet:1422), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000037	Male pseudohermaphroditism
HP:0000252	Microcephaly
HP:0000400	Macrotia
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000506	Telecanthus
HP:0000567	Chorioretinal coloboma
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000588	Optic disc coloboma
HP:0000616	Miosis
HP:0000774	Narrow chest
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001511	Intrauterine growth retardation
HP:0001591	Bell-shaped thorax
HP:0002069	Bilateral tonic-clonic seizure
HP:0002164	Nail dysplasia
HP:0002644	Abnormal pelvic girdle bone morphology
HP:0002983	Micromelia
HP:0003043	Abnormal shoulder morphology
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003394	Muscle spasm
HP:0003510	Severe short stature
HP:0004330	Increased skull ossification
HP:0005621	Trapezoidal vertebral body

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001733_1	Schizophrenia	6.000000e-09
GCST003186_1	Cardiovascular disease in hypertension (ACE inhibitor interaction)	8.000000e-06
GCST004102_2	Body mass index (change over time) in lung cancer or chronic obstructive pulmonary disease	3.000000e-07
GCST004105_4	Body mass index (change over time) in chronic obstructive pulmonary disease	3.000000e-06
GCST004863_49	Mosquito bite size	2.000000e-06
GCST004866_6	Alopecia areata	2.000000e-06
GCST005529_64	Ankylosing spondylitis	6.000000e-06
GCST005529_7	Ankylosing spondylitis	4.000000e-07
GCST006288_176	Heel bone mineral density	6.000000e-07
GCST006288_612	Heel bone mineral density	1.000000e-11
GCST006309_1	Post bronchodilator percent predicted FEV1 in smoking	4.000000e-06
GCST006310_1	Post bronchodilator FEV1/FVC ratio in smoking	2.000000e-07
GCST006979_969	Heel bone mineral density	5.000000e-27
GCST008759_34	Intake of total sugars	7.000000e-06
GCST008830_2	Neurofibrillary tangles	9.000000e-06
GCST010244_168	Triglyceride levels	2.000000e-08
GCST012194_1	Obsessive-compulsive traits	4.000000e-06

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0005937	longitudinal BMI measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0009270	heel bone mineral density
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0010158	sugar consumption measurement
EFO:0006797	neurofibrillary tangles measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536123	Nivelon Nivelon Mabille syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296243 (SINGLE PROTEIN)

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

ChEMBL bioactivities

52 potent at pChembl≥5 of 57 total, top 47 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.42	Ki	38	nM	CHEMBL5421720
7.12	IC50	76	nM	CHEMBL5421720
7.00	EC50	99	nM	CHEMBL5421720
6.75	IC50	180	nM	CHEMBL5560567
6.70	IC50	200	nM	CHEMBL4284857
6.34	IC50	460	nM	CHEMBL4287920
6.31	IC50	490	nM	CHEMBL5398039
6.24	IC50	570	nM	CHEMBL4287920
6.24	EC50	580	nM	CHEMBL5417899
6.24	EC50	580	nM	CHEMBL4284857
6.17	IC50	680	nM	CHEMBL4284857
6.12	IC50	750	nM	CHEMBL5421720
6.10	EC50	800	nM	CHEMBL5417298
6.07	IC50	850	nM	CHEMBL3133036
5.97	IC50	1080	nM	CHEMBL4284857
5.93	EC50	1170	nM	CHEMBL4287920
5.93	EC50	1180	nM	CHEMBL5398039
5.89	EC50	1290	nM	CHEMBL5414732
5.88	IC50	1330	nM	CHEMBL5398039
5.84	IC50	1440	nM	CHEMBL5411797
5.80	EC50	1580	nM	CHEMBL5432414
5.69	IC50	2050	nM	CHEMBL4287920
5.67	IC50	2130	nM	CHEMBL4287920
5.63	IC50	2350	nM	CHEMBL5404818
5.59	IC50	2580	nM	CHEMBL4284857
5.59	EC50	2590	nM	CHEMBL5394179
5.56	IC50	2770	nM	CHEMBL5417298
5.54	EC50	2920	nM	CHEMBL4293657
5.53	EC50	2960	nM	CHEMBL5426855
5.51	IC50	3070	nM	CHEMBL5566848
5.43	IC50	3710	nM	CHEMBL5432414
5.38	IC50	4220	nM	CHEMBL5421034
5.37	EC50	4250	nM	CHEMBL5432251
5.34	EC50	4560	nM	CHEMBL5420044
5.33	IC50	4620	nM	CHEMBL5432251
5.32	IC50	4790	nM	CHEMBL5403413
5.27	IC50	5340	nM	CHEMBL5420044
5.26	EC50	5460	nM	CHEMBL5407213
5.22	IC50	5970	nM	CHEMBL5404818
5.22	IC50	6020	nM	CHEMBL5394179
5.19	EC50	6440	nM	CHEMBL5421034
5.18	IC50	6550	nM	CHEMBL4293657
5.15	IC50	7010	nM	CHEMBL5416048
5.13	IC50	7450	nM	CHEMBL5414732
5.13	Ki	7400	nM	CHEMBL3133036
5.10	IC50	7980	nM	CHEMBL5417899
5.09	IC50	8090	nM	CHEMBL5420830

PubChem BioAssay actives

50 with measured affinity, of 151 total; 23 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
2-(2-methylpropylamino)-1-[(4R)-4-(6-methyl-2-pyridinyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1984335: Inhibition of HHAT (unknown origin) assessed as inhibition constant by Pal-CoA Competitive assay	ki	0.0380	uM
1-[4-[(4-chloro-3-methylphenoxy)methyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]-2-(prop-2-enylamino)ethanone	2084104: Inhibition of His-tagged HHAT (unknown origin) transfected in HEK293FT cells	ic50	0.1800	uM
2-(2-methylbutylamino)-1-[4-(6-methyl-2-pyridinyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1525381: Inhibition of 3C-FLAG/His8-tagged human HHAT expressed in HEK293 cells assessed as reduction in enzyme-mediated sonic hedgehog (1 to 11 residues) palmitoylation by click-ELISA method	ic50	0.2000	uM
2-(2-methylbutylamino)-1-[4-(3-methylphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	2084106: Inhibition of HHAT (unknown origin)	ic50	0.4600	uM
2-(2-methylpropylamino)-1-[4-(6-methyl-2-pyridinyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1984336: Inhibition of HHAT in human HEK293a SHH+ cells assessed as inhibition SHH-YnPal tagging measured after 7 hrs by cell-based tagging assay	ic50	0.4900	uM
2-(2-methylbutylamino)-1-(4-pyridin-2-yl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	0.5800	uM
2-(2-methylpropylamino)-1-[(1S)-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	0.8000	uM
2-(2-methylbutylamino)-1-[4-[(3-methylphenoxy)methyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1525380: Inhibition of HA/FLAG/His-tagged HHAT (unknown origin) expressed in 293FT cells assessed as enzyme-mediated sonic hedgehog palmitoylation incubated for 20 mins followed by [125I]iodo-palmitoyl CoA and Shh biotinylated peptide and measured after 1 hr by Scintillation proximity assay	ic50	0.8500	uM
1-[(4R)-4-(6-methyl-2-pyridinyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	1.2900	uM
2-[[(2R)-2-methylbutyl]amino]-1-[(4R)-4-[(3-methylphenoxy)methyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1984331: Inhibition of human recombinant HHAT using SHH-FAM peptide as substrate for 30 mins by acylation coupled lipophilic induction of polarization (acyl-cLIP) assay	ic50	1.4400	uM
2-[[(2S)-2-methylbutyl]amino]-1-[4-(6-methyl-2-pyridinyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	1.5800	uM
1-[4-[(4-chlorophenoxy)methyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]-2-(prop-2-enylamino)ethanone	1984336: Inhibition of HHAT in human HEK293a SHH+ cells assessed as inhibition SHH-YnPal tagging measured after 7 hrs by cell-based tagging assay	ic50	2.3500	uM
2-(2-methylpropylamino)-1-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	2.5900	uM
1-(4-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2-(prop-2-enylamino)ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	2.9200	uM
1-[4-(3-methylphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]prop-2-en-1-one	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	2.9600	uM
1-[4-[(4-chloro-3-methylphenoxy)methyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]-2-(3-methoxypropylamino)ethanone	2084104: Inhibition of His-tagged HHAT (unknown origin) transfected in HEK293FT cells	ic50	3.0700	uM
1-(7-chloro-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-(2-methylbutylamino)ethanone	1984331: Inhibition of human recombinant HHAT using SHH-FAM peptide as substrate for 30 mins by acylation coupled lipophilic induction of polarization (acyl-cLIP) assay	ic50	4.2200	uM
2-(3-methylbutylamino)-1-[4-(6-methyl-2-pyridinyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	4.2500	uM
1-(4-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	4.5600	uM
1-[4-(2-hydroxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]-2-(2-methylbutylamino)ethanone	1984331: Inhibition of human recombinant HHAT using SHH-FAM peptide as substrate for 30 mins by acylation coupled lipophilic induction of polarization (acyl-cLIP) assay	ic50	4.7900	uM
1-[4-(6-methyl-2-pyridinyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone	1984337: Inhibition of HHAT in human HEK293a SHH+ cells incubated with compound for 24 hrs followed by transferred into SHH-Light2 cells cellular incubated for 48 hrs by Renilla/Firefly luciferase reporter assay	ec50	5.4600	uM
2-(2-methylbutylamino)-1-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone	1984331: Inhibition of human recombinant HHAT using SHH-FAM peptide as substrate for 30 mins by acylation coupled lipophilic induction of polarization (acyl-cLIP) assay	ic50	7.0100	uM
1-[4-(2-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]-2-(2-methylbutylamino)ethanone	1984331: Inhibition of human recombinant HHAT using SHH-FAM peptide as substrate for 30 mins by acylation coupled lipophilic induction of polarization (acyl-cLIP) assay	ic50	8.0900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, affects expression	8
Aflatoxin B1	decreases methylation, affects expression, decreases expression	4
Valproic Acid	decreases methylation, affects expression, decreases expression	3
sodium arsenite	increases expression, increases abundance	2
entinostat	decreases expression, affects cotreatment	2
Arsenic	affects methylation, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	affects methylation	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Temozolomide	affects response to substance	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vehicle Emissions	decreases expression, increases abundance	1
Carmustine	affects response to substance	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Demecolcine	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4256993	Binding	Inhibition of HA/FLAG/His-tagged Hhat (unknown origin) expressed in human 293T cells at 12.5 uM using biotinylated Shh peptide as substrate pretreated for 20 mins followed by [125I]-iodo-palitoylCoA/substrate addition measured after 1 hr by	Treatment of pancreatic and related cancers with 5-acyl-6,7-dihydrothieno[3,2-c]pyridines

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders