ZDHHC9

Summary

ZDHHC9 (zDHHC palmitoyltransferase 9, HGNC:18475) is a protein-coding gene on chromosome Xq26.1, encoding Palmitoyltransferase ZDHHC9 (Q9Y397). Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, GSDMD, HRAS, NRAS and CGAS. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes an integral membrane protein that is a member of the zinc finger DHHC domain-containing protein family. The encoded protein forms a complex with golgin subfamily A member 7 and functions as a palmitoyltransferase. This protein specifically palmitoylates HRAS and NRAS. Mutations in this gene are associated with X-linked cognitive disability. Alternate splicing results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 51114 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic X-linked intellectual disability Raymond type (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 379 total — 9 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_016032

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18475
Approved symbol	ZDHHC9
Name	zDHHC palmitoyltransferase 9
Location	Xq26.1
Locus type	gene with protein product
Status	Approved
Aliases	ZNF379, CGI-89, ZNF380, DHHC9
Ensembl gene	ENSG00000188706
Ensembl biotype	protein_coding
OMIM	300646
Entrez	51114

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 22 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000357166, ENST00000371064, ENST00000406492, ENST00000433917, ENST00000491039, ENST00000860166, ENST00000860167, ENST00000860168, ENST00000860169, ENST00000860170, ENST00000860171, ENST00000860172, ENST00000860173, ENST00000939982, ENST00000939983, ENST00000939984, ENST00000939985, ENST00000939986, ENST00000939987, ENST00000939988, ENST00000939989, ENST00000966617, ENST00000966618

RefSeq mRNA: 2 — MANE Select: NM_016032 NM_001008222, NM_016032

CCDS: CCDS35395

Canonical transcript exons

ENST00000357166 — 11 exons

Exon	Start	End
ENSE00001383505	129810905	129811001
ENSE00001383874	129811406	129811509
ENSE00001385003	129823679	129823837
ENSE00001385758	129814658	129814795
ENSE00001389851	129828981	129829141
ENSE00001427357	129843259	129843326
ENSE00001430041	129841779	129842080
ENSE00001454265	129812718	129812820
ENSE00001454268	129813677	129813725
ENSE00001548753	129843696	129843886
ENSE00001910038	129803288	129806486

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 97.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.6264 / max 344.8438, expressed in 1779 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200450	21.2214	1769
200451	1.5502	1043
200449	1.0216	433
200448	0.5297	279
200445	0.1211	42
200446	0.1013	37
200447	0.0811	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	97.34	gold quality
inferior vagus X ganglion	UBERON:0005363	96.43	gold quality
kidney epithelium	UBERON:0004819	96.42	gold quality
upper arm skin	UBERON:0004263	95.48	gold quality
lateral globus pallidus	UBERON:0002476	94.47	gold quality
subthalamic nucleus	UBERON:0001906	94.11	gold quality
ileal mucosa	UBERON:0000331	93.98	gold quality
globus pallidus	UBERON:0001875	93.97	gold quality
medial globus pallidus	UBERON:0002477	93.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.77	gold quality
spinal cord	UBERON:0002240	93.50	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.99	gold quality
ventral tegmental area	UBERON:0002691	92.59	gold quality
cortical plate	UBERON:0005343	92.40	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.20	gold quality
pons	UBERON:0000988	91.84	gold quality
medulla oblongata	UBERON:0001896	91.70	gold quality
midbrain	UBERON:0001891	91.57	gold quality
substantia nigra	UBERON:0002038	91.47	gold quality
substantia nigra pars compacta	UBERON:0001965	91.05	gold quality
stromal cell of endometrium	CL:0002255	90.89	gold quality
skin of leg	UBERON:0001511	90.87	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.66	gold quality
postcentral gyrus	UBERON:0002581	90.17	gold quality
superior vestibular nucleus	UBERON:0007227	90.11	gold quality
Ammon’s horn	UBERON:0001954	90.02	gold quality
lower lobe of lung	UBERON:0008949	89.79	gold quality
parietal lobe	UBERON:0001872	89.62	gold quality
zone of skin	UBERON:0000014	89.52	gold quality
pericardium	UBERON:0002407	89.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.67
E-MTAB-4850	no	229.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

157 targeting ZDHHC9, 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-6873-3P	100.00	71.42	2626
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 14)

• Data show that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. (PMID:16000296)
• DHHC9 is a gastrointestinal-related protein highly expressed in microsatellite stable colorectal cancers. (PMID:17519897)
• Studies indicate that mutations in DHHC9 were associated with X-linked mental retardation. (PMID:21388813)
• MMSA-1 may play a pivotal role in multiple myeloma proliferation and osteolysis destruction. (PMID:22230506)
• Data indicate that sp-Erf2/zDHHC9 palmitoylates Ras proteins in a highly selective manner in the trans-Golgi compartment to facilitate PM targeting via the trans-Golgi network, a role that is most certainly critical for Ras-driven tumorigenesis. (PMID:24248599)
• Two missense mutation, R148W and P150S,of zDHHC9, affecting the autopalmitoylation is associated with the X-linked intellectual disability. (PMID:24811172)
• ZDHHC9 gene mutation is associated with Lujan-Fryns syndrome. (PMID:26358559)
• Report demonstrated that MMSA-1 is specifically expressed in multiple myeloma patients and its upregulation is associated with unfavorable clinical features and poor prognosis. (PMID:26493349)
• studies suggest that ZDHHC9 may serve as a safe and effective target for developing therapies against NRAS-driven cancers (PMID:26493479)
• Data demonstrate that ZDHHC9 mutations are associated with reductions in cortical thickness and white matter microstructural integrity, particularly in regions and networks known to contribute to language function. (PMID:27747153)
• The results demonstrate that a mutation in a ZDHHC9 mutation impacts upon white matter organization across the whole-brain, but also shows regionally specific effects, according to variation in gene expression. (PMID:28168288)
• De novo ZDHHC9 mutation was identified in a patient with X-linked intellectual disability. (PMID:28687527)
• DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis. (PMID:34620861)
• Involvement of ZDHHC9 in lung adenocarcinoma: regulation of PD-L1 stability via palmitoylation. (PMID:37002491)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	zdhhc9	ENSDARG00000060515
mus_musculus	Zdhhc9	ENSMUSG00000036985
rattus_norvegicus	Zdhhc9	ENSRNOG00000004581
drosophila_melanogaster	Dnz1	FBGN0027453
drosophila_melanogaster	CG1407	FBGN0033474
drosophila_melanogaster	CG17287	FBGN0034202
caenorhabditis_elegans	dhhc-7	WBGENE00007637
caenorhabditis_elegans	dhhc-12	WBGENE00010323
caenorhabditis_elegans	dhhc-2	WBGENE00012948
caenorhabditis_elegans		WBGENE00014075
caenorhabditis_elegans		WBGENE00016620
caenorhabditis_elegans		WBGENE00020066

Paralogs (17): ZDHHC6 (ENSG00000023041), ZDHHC15 (ENSG00000102383), ZDHHC2 (ENSG00000104219), ZDHHC4 (ENSG00000136247), ZDHHC7 (ENSG00000153786), ZDHHC1 (ENSG00000159714), ZDHHC12 (ENSG00000160446), ZDHHC3 (ENSG00000163812), ZDHHC19 (ENSG00000163958), ZDHHC14 (ENSG00000175048), ZDHHC21 (ENSG00000175893), ZDHHC22 (ENSG00000177108), ZDHHC20 (ENSG00000180776), ZDHHC23 (ENSG00000184307), ZDHHC11 (ENSG00000188818), ZDHHC18 (ENSG00000204160), ZDHHC11B (ENSG00000206077)

Protein

Protein identifiers

Palmitoyltransferase ZDHHC9 — Q9Y397 (reviewed: Q9Y397)

Alternative names: Zinc finger DHHC domain-containing protein 9, Zinc finger protein 379, Zinc finger protein 380

All UniProt accessions (3): Q9Y397, H0Y6K6, Q5JYE8

UniProt curated annotations — full annotation on UniProt →

Function. Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, GSDMD, HRAS, NRAS and CGAS. The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS. May have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein-coupled receptor signaling. Acts as a regulator of innate immunity by catalyzing palmitoylation of CGAS, thereby promoting CGAS homodimerization and cyclic GMP-AMP synthase activity. Activates pyroptosis by catalyzing palmitoylation of gasdermin-D (GSDMD), thereby promoting membrane translocation and pore formation of GSDMD. (Microbial infection) Through a sequential action with ZDHHC20, rapidly and efficiently palmitoylates SARS coronavirus-2/SARS-CoV-2 spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell.

Subunit / interactions. Interacts with GOLGA7.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Tissue specificity. Highly expressed in kidney, skeletal muscle, brain, lung and liver. Absent in thymus, spleen and leukocytes.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Raymond type (MRXSR) [MIM:300799] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Some MRXSR patients show additional features, including marfanoid habitus, epilepsy, facial dysmorphism, hypotonia, and behavioral problems. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The DHHC domain is required for palmitoyltransferase activity.

Similarity. Belongs to the DHHC palmitoyltransferase family. ERF2/ZDHHC9 subfamily.

RefSeq proteins (2): NP_001008223, NP_057116* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001594	Palmitoyltrfase_DHHC	Domain
IPR039859	PFA4/ZDH16/20/ERF2-like	Family

Pfam: PF01529

Enzyme classification (BRENDA):

• EC 2.3.1.225 — protein S-acyltransferase (BRENDA: 9 organisms, 108 substrates, 15 inhibitors, 6 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PALMITOYL-COA	0.0052–0.0059	2
[N-MYRISTOYLATED GLY-CYS-GLY TRIPEPTIDE]-L-CYSTE	0.0008–0.0013	2

Catalyzed reactions (Rhea), 1 shown:

• L-cysteinyl-[protein] + hexadecanoyl-CoA = S-hexadecanoyl-L-cysteinyl-[protein] + CoA (RHEA:36683)

UniProt features (43 total): helix 10, strand 7, topological domain 5, turn 5, transmembrane region 4, sequence conflict 3, compositionally biased region 2, sequence variant 2, chain 1, domain 1, region of interest 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8HF3	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y397-F1	84.84	0.70

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): 169 (s-palmitoyl cysteine intermediate)

Mutagenesis-validated functional residues (1):

Position	Phenotype
169	abolishes palmitoyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9648002	RAS processing
R-HSA-9694548	Maturation of spike protein

MSigDB gene sets: 323 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_INFLAMMATORY_RESPONSE, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_PROTEIN_TARGETING, TATTATA_MIR374, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_PEPTIDYL_CYSTEINE_MODIFICATION, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, SOX9_B1, GOBP_LIPOPROTEIN_BIOSYNTHETIC_PROCESS

GO Biological Process (15): MAPK cascade (GO:0000165), protein targeting to membrane (GO:0006612), peptidyl-L-cysteine S-palmitoylation (GO:0018230), post-translational protein modification (GO:0043687), host-mediated activation of viral process (GO:0044794), protein maturation (GO:0051604), positive regulation of pyroptotic inflammatory response (GO:0140639), positive regulation of cGAS/STING signaling pathway (GO:0141111), non-canonical inflammasome complex assembly (GO:0160075), negative regulation of T-helper 1 type immune response (GO:0002826), ubiquitin-dependent protein catabolic process (GO:0006511), virion attachment to host cell (GO:0019062), ERAD pathway (GO:0036503), cGAS/STING signaling pathway (GO:0140896), pyroptotic cell death (GO:0141201)

GO Molecular Function (6): palmitoyltransferase activity (GO:0016409), protein-cysteine S-palmitoyltransferase activity (GO:0019706), Ras palmitoyltransferase activity (GO:0043849), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (8): Golgi membrane (GO:0000139), palmitoyltransferase complex (GO:0002178), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RAF/MAP kinase cascade	1
Translation of Structural Proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
pyroptotic inflammatory response	2
bounding membrane of organelle	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
intracellular signaling cassette	1
protein targeting	1
establishment of protein localization to membrane	1
peptidyl-S-diacylglycerol-L-cysteine biosynthetic process from peptidyl-cysteine	1
protein palmitoylation	1
protein modification process	1
host-mediated perturbation of viral process	1
gene expression	1
protein metabolic process	1
positive regulation of inflammatory response	1
regulation of cytoplasmic pattern recognition receptor signaling pathway	1
positive regulation of pattern recognition receptor signaling pathway	1
cGAS/STING signaling pathway	1
positive regulation of intracellular signal transduction	1
protein-containing complex assembly	1
negative regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
viral life cycle	1
adhesion of symbiont to host cell	1
virion binding	1
host cell surface binding	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
cytoplasmic pattern recognition receptor signaling pathway	1
programmed cell death	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
palmitoyltransferase activity	1
protein-cysteine S-acyltransferase activity	1
protein-cysteine S-palmitoyltransferase activity	1
binding	1

Protein interactions and networks

STRING

872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZDHHC9	GOLGA7	Q7Z5G4	999
ZDHHC9	ZFP36L2	P47974	912
ZDHHC9	NRAS	P01111	901
ZDHHC9	GOLGA3	Q08378	804
ZDHHC9	HRAS	P01112	734
ZDHHC9	LYPLA1	O75608	487
ZDHHC9	UPF3B	Q9BZI7	483
ZDHHC9	ICMT	O60725	473
ZDHHC9	PPT1	P50897	445
ZDHHC9	ABHD17A	Q96GS6	420
ZDHHC9	BRWD3	Q6RI45	420
ZDHHC9	LYPLA2	O95372	419
ZDHHC9	ZC4H2	Q9NQZ6	413
ZDHHC9	GOLGA7B	Q2TAP0	408
ZDHHC9	GLTP	Q9NZD2	402

IntAct

91 interactions, top by confidence:

A	B	Type	Score
ZDHHC9	CREB3	psi-mi:“MI:0915”(physical association)	0.560
SLC7A1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TSPAN3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3B1	psi-mi:“MI:0914”(association)	0.530
GDPD5	GOLIM4	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
IL20RB	B4GALT5	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TCIRG1	AP3D1	psi-mi:“MI:0914”(association)	0.530
CHRNA9	CHEK1	psi-mi:“MI:0914”(association)	0.530
TSPAN5	SC5D	psi-mi:“MI:0914”(association)	0.530
IL4R	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
ZDHHC9		psi-mi:“MI:0915”(physical association)	0.370

BioGRID (82): ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), CREB3 (Two-hybrid), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IDP3, B3DN87, E7F587, E7FH11, F1Q7H8, F1QGD2, F1QXD3, F1R013, F1RE57, O74384, O80685, P42836, P59268, Q03289, Q06551, Q0VC89, Q0WQK2, Q2TGJ1, Q2TGJ4, Q58DA8, Q5BLG4, Q5FWL7, Q5M757, Q5PNZ1, Q5R5J8, Q5W0Z9, Q5Y5T1, Q5Y5T2, Q6BHT4, Q6CPU8, Q6CQB5, Q6CRV3, Q6DHI1, Q6FMP5, Q6FSS4, Q6FW70, Q75AW7, Q7ZVN4, Q8BGJ0, Q8VYP5

Diamond homologs: A0A0R4IDP3, A2CEX1, A2VEY9, A5WVX9, B3DN87, C8VCL4, E1BLT8, E7F021, E7F587, E7FBS9, E7FH11, E9PTT0, E9QCD3, F1Q7H8, F1QAM1, F1QHM7, F1QX91, F1QXD3, F1R013, F1RE57, J9VJ99, O60069, O74384, O80685, P42836, P59267, P59268, Q04629, Q0VC89, Q10L01, Q2TGJ1, Q2TGJ4, Q2TGK3, Q2THW7, Q2THW8, Q2THW9, Q2THX0, Q2THX1, Q4R690, Q4WZL8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ZDHHC9	“up-regulates activity”	HRAS	palmitoylation
GOLGA7	“up-regulates activity”	ZDHHC9	binding
ZDHHC9	“up-regulates activity”	NRAS	palmitoylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	9
Uncertain significance	114
Likely benign	103
Benign	40

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
10709	NM_016032.4(ZDHHC9):c.172_175del (p.Arg58fs)	Pathogenic
10710	NM_016032.4(ZDHHC9):c.167+5G>C	Pathogenic
10712	NM_016032.4(ZDHHC9):c.448C>T (p.Pro150Ser)	Pathogenic
2126777	NM_016032.4(ZDHHC9):c.361C>T (p.Arg121Ter)	Pathogenic
504233	NM_016032.4(ZDHHC9):c.328+1G>A	Pathogenic
521595	NM_016032.4(ZDHHC9):c.679del (p.Val226_Leu227insTer)	Pathogenic
524052	NM_016032.4(ZDHHC9):c.717_738del (p.Val240fs)	Pathogenic
873026	NC_000023.10:g.(?128946967)(128948896_?)del	Pathogenic
985486	NM_016032.4(ZDHHC9):c.743dup (p.Leu249fs)	Pathogenic
2575978	NM_016032.4(ZDHHC9):c.792G>A (p.Trp264Ter)	Likely pathogenic
3062259	NM_016032.4(ZDHHC9):c.167+1G>A	Likely pathogenic
3640685	NM_016032.4(ZDHHC9):c.488-2A>G	Likely pathogenic
3724442	NM_016032.4(ZDHHC9):c.777+1G>A	Likely pathogenic
418668	NM_016032.4(ZDHHC9):c.251T>C (p.Leu84Ser)	Likely pathogenic
4795936	NM_016032.4(ZDHHC9):c.811C>T (p.Gln271Ter)	Likely pathogenic
619977	NM_016032.4(ZDHHC9):c.268G>A (p.Asp90Asn)	Likely pathogenic
931980	NM_016032.4(ZDHHC9):c.852dup (p.Glu285Ter)	Likely pathogenic
981419	NM_016032.4(ZDHHC9):c.881+1G>C	Likely pathogenic

SpliceAI

1621 predictions. Top by Δscore:

Variant	Effect	Δscore
X:129810903:A:AC	donor_gain	1.0000
X:129810904:C:CC	donor_gain	1.0000
X:129810904:CTGGG:C	donor_gain	1.0000
X:129811000:CA:C	acceptor_gain	1.0000
X:129811433:T:TA	donor_gain	1.0000
X:129812785:C:CT	acceptor_gain	1.0000
X:129813634:G:C	donor_gain	1.0000
X:129813659:A:AC	donor_gain	1.0000
X:129813660:C:CC	donor_gain	1.0000
X:129813660:CTG:C	donor_gain	1.0000
X:129814656:A:AC	donor_gain	1.0000
X:129814657:C:CG	donor_gain	1.0000
X:129823673:ACT:A	donor_loss	1.0000
X:129823674:CTC:C	donor_loss	1.0000
X:129823677:A:AT	donor_loss	1.0000
X:129823677:ACC:A	donor_gain	1.0000
X:129823678:CCC:C	donor_gain	1.0000
X:129823678:CCCA:C	donor_gain	1.0000
X:129823833:AGCTT:A	acceptor_gain	1.0000
X:129823835:CTT:C	acceptor_gain	1.0000
X:129823836:TT:T	acceptor_gain	1.0000
X:129823838:C:A	acceptor_loss	1.0000
X:129823838:C:CC	acceptor_gain	1.0000
X:129823847:A:T	acceptor_gain	1.0000
X:129828976:CTCA:C	donor_loss	1.0000
X:129828977:TCAC:T	donor_loss	1.0000
X:129828978:CA:C	donor_loss	1.0000
X:129828979:ACCTA:A	donor_loss	1.0000
X:129828980:CCTAT:C	donor_gain	1.0000
X:129828984:T:C	donor_gain	1.0000

AlphaMissense

2398 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:129811441:G:C	N282K	1.000
X:129811441:G:T	N282K	1.000
X:129811497:A:G	W264R	1.000
X:129811497:A:T	W264R	1.000
X:129811504:T:A	K261N	1.000
X:129811504:T:G	K261N	1.000
X:129811505:T:A	K261I	1.000
X:129811506:T:C	K261E	1.000
X:129811508:A:T	I260N	1.000
X:129812721:T:A	E258D	1.000
X:129812721:T:G	E258D	1.000
X:129812722:T:A	E258V	1.000
X:129812722:T:G	E258A	1.000
X:129812723:C:T	E258K	1.000
X:129812724:A:C	N257K	1.000
X:129812724:A:T	N257K	1.000
X:129812728:G:A	T256I	1.000
X:129812728:G:T	T256N	1.000
X:129812731:G:A	T255I	1.000
X:129812749:A:G	L249P	1.000
X:129812749:A:T	L249H	1.000
X:129812757:A:C	H246Q	1.000
X:129812757:A:T	H246Q	1.000
X:129812758:T:C	H246R	1.000
X:129812759:G:C	H246D	1.000
X:129812759:G:T	H246N	1.000
X:129812760:A:C	F245L	1.000
X:129812760:A:T	F245L	1.000
X:129812761:A:G	F245S	1.000
X:129812762:A:G	F245L	1.000

dbSNP variants (sampled 300 via entrez): RS1000001949 (X:129828147 T>C), RS1000037294 (X:129843400 C>G), RS1000064227 (X:129838270 G>A), RS1000114799 (X:129837672 G>A), RS1000165067 (X:129831341 C>A), RS1000438380 (X:129828454 T>G), RS1000450049 (X:129835521 G>A,T), RS1000570389 (X:129837905 G>A), RS1000633380 (X:129845493 T>A), RS1001165880 (X:129809431 G>A), RS1001170555 (X:129840092 G>C), RS1001450128 (X:129809839 A>C), RS1001457611 (X:129812244 C>T), RS1001563554 (X:129813037 T>C), RS1001615022 (X:129811749 C>T)

Disease associations

OMIM: gene MIM:300646 | disease phenotypes: MIM:300799

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Raymond type	Definitive	X-linked
X-linked intellectual disability with marfanoid habitus	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Raymond type	Definitive	XL

Mondo (5): syndromic X-linked intellectual disability Raymond type (MONDO:0010427), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), autism spectrum disorder (MONDO:0005258), X-linked intellectual disability with marfanoid habitus (MONDO:0010655)

Orphanet (2): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000053	Macroorchidism
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000275	Narrow face
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000486	Strabismus
HP:0000678	Dental crowding
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000738	Hallucinations
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0001156	Brachydactyly
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001382	Joint hypermobility
HP:0001417	X-linked inheritance
HP:0001519	Disproportionate tall stature
HP:0001608	Abnormality of the voice
HP:0001611	Hypernasal speech

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_95	Refractive error	4.000000e-10

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C537724	Lujan Fryns syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067465 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects cotreatment, increases abundance, increases expression	3
Valproic Acid	affects cotreatment, decreases expression, increases methylation	3
Cisplatin	decreases expression, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	increases expression	1
Fluorouracil	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methapyrilene	increases methylation	1
Dihydrotestosterone	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Antirheumatic Agents	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5524597	Binding	Binding affinity to ZDHHC9 (unknown origin) assessed as inhibition constant	Modulators for palmitoylation of proteins and small molecules. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TZ09	HAP1 ZDHHC9 (-) 1	Cancer cell line	Male
CVCL_TZ10	HAP1 ZDHHC9 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

298 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
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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