DDHD2

Summary

DDHD2 (DDHD domain containing 2, HGNC:29106) is a protein-coding gene on chromosome 8p11.23, encoding Triacylglycerol hydrolase DDHD2 (O94830). Diacylglycerol (DAG) and triacylglycerol (TAG) lipase required for proper lipid homeostasis in the central nervous system.

This gene encodes a phospholipase enzyme containing sterile-alpha-motif (SAM), WWE, and DDHD domains. This protein participates in membrane trafficking between the endoplastic reticulum and the Golgi body. Mutations in this gene can cause autosomal recessive spastic paraplegia 54. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23259 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 54 (Definitive, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 448 total — 22 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes
• MANE Select transcript: NM_015214

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29106
Approved symbol	DDHD2
Name	DDHD domain containing 2
Location	8p11.23
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0725, SPG54, p125B, iPLA1gamma, iPLA1γ
Ensembl gene	ENSG00000085788
Ensembl biotype	protein_coding
OMIM	615003
Entrez	23259

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 33 protein_coding, 7 retained_intron, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000397166, ENST00000517385, ENST00000519857, ENST00000520176, ENST00000520272, ENST00000524545, ENST00000526071, ENST00000526144, ENST00000526237, ENST00000526370, ENST00000527415, ENST00000527834, ENST00000528148, ENST00000528358, ENST00000528504, ENST00000528613, ENST00000528888, ENST00000529642, ENST00000529845, ENST00000529872, ENST00000531344, ENST00000532106, ENST00000532222, ENST00000533100, ENST00000853780, ENST00000853781, ENST00000853782, ENST00000853783, ENST00000853784, ENST00000853785, ENST00000853786, ENST00000853787, ENST00000853788, ENST00000853789, ENST00000853790, ENST00000935428, ENST00000935429, ENST00000970138, ENST00000970139, ENST00000970140, ENST00000970141, ENST00000970142, ENST00000970143, ENST00000970144, ENST00000970145, ENST00000970146, ENST00000970147

RefSeq mRNA: 7 — MANE Select: NM_015214 NM_001164232, NM_001164234, NM_001362911, NM_001362912, NM_001362913, NM_001362914, NM_015214

CCDS: CCDS34883

Canonical transcript exons

ENST00000397166 — 18 exons

Exon	Start	End
ENSE00002155685	38249708	38249803
ENSE00002190460	38260600	38262836
ENSE00003503250	38234394	38234584
ENSE00003508235	38251912	38252028
ENSE00003541400	38252722	38252824
ENSE00003667453	38252132	38252287
ENSE00003695665	38232987	38233214
ENSE00004282972	38260040	38260147
ENSE00004282973	38245742	38245950
ENSE00004282974	38247713	38247835
ENSE00004282975	38242250	38242385
ENSE00004282976	38252957	38253127
ENSE00004282977	38253556	38253718
ENSE00004282978	38231585	38231859
ENSE00004282979	38238089	38238209
ENSE00004282980	38237538	38237627
ENSE00004282981	38246233	38246300
ENSE00004282982	38240275	38240364

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.2409 / max 270.4276, expressed in 1807 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88481	19.7893	1800
88482	2.4517	1067

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	99.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.90	gold quality
middle temporal gyrus	UBERON:0002771	98.20	gold quality
primary visual cortex	UBERON:0002436	97.39	gold quality
calcaneal tendon	UBERON:0003701	97.28	gold quality
postcentral gyrus	UBERON:0002581	96.76	gold quality
superior frontal gyrus	UBERON:0002661	96.67	gold quality
occipital lobe	UBERON:0002021	96.59	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.31	gold quality
parietal lobe	UBERON:0001872	96.23	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.20	gold quality
prefrontal cortex	UBERON:0000451	96.05	gold quality
tendon	UBERON:0000043	96.00	gold quality
sural nerve	UBERON:0015488	95.85	gold quality
entorhinal cortex	UBERON:0002728	95.61	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.60	gold quality
pons	UBERON:0000988	95.48	gold quality
corpus callosum	UBERON:0002336	95.45	gold quality
colonic epithelium	UBERON:0000397	95.41	gold quality
spinal cord	UBERON:0002240	95.33	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.31	gold quality
cerebellar vermis	UBERON:0004720	95.30	gold quality
cortical plate	UBERON:0005343	95.18	gold quality
frontal cortex	UBERON:0001870	95.03	gold quality
ganglionic eminence	UBERON:0004023	94.97	gold quality
cranial nerve II	UBERON:0000941	94.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.88	gold quality
neocortex	UBERON:0001950	94.74	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.73	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting DDHD2, 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-9-5P	100.00	72.28	2361
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-95-5P	99.89	72.17	3973

Literature-anchored findings (GeneRIF, showing 20)

• Data show that FGFR1 and DDHD2 at 8p12 cooperated functionally with MYC, whereas CCND1 and ZNF703 cooperated with a dominant negative form of TP53. (PMID:19330026)
• KIAA0725p is localized in the Golgi [KIAA0725p] (PMID:20932832)
• KIAAO725p is targeted to specific organelle membranes in a phosphoinositide-dependent manner. (PMID:22922100)
• mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease. (PMID:23176823)
• Two deleterious mutations in the phospholipase DDHD2 gene in two families with complicated Hereditary spastic paraplegias. (PMID:23486545)
• The DDHD2 gene shows a low mutation frequency in a general population of complicated hereditary spastic paraparesis (PMID:24337409)
• study reports two Italian brothers with autosomal recessive hereditary spastic paraplegia with thin corpus callosum due to two deleterious compound heterozygous missense mutations that have been identified in the DDHD2 gene by exome sequencing (PMID:24517879)
• Three missense mutations including p.Val220Phe of DDHD2 significantly reduced PLA1 activity and indicated that the loss of PLA1 activity significantly contributes to SPG54 pathogenicity. (PMID:25417924)
• Our results provide an extensive genome wide set of targets for miR-503, miR-103, and miR-494, and suggest that miR-503 may act as a tumor suppressor in breast cancer by its direct non-canonical targeting of DDHD2. (PMID:25653011)
• Truncating mutation has been found in the DDHD2 gene in a large consanguineous family with hereditary spastic paraplegia and intellectual disability. (PMID:26113134)
• A set of HSP-related mutations in DDHD2 disrupt triglyceride hydrolase activity in vitro and impair the capacity of DDHD2 to protect cells from lipid droplet accumulation after exposure to free fatty acid.Genetic inactivation of DDHD2 from HSP-associated mutations perturbs lipid homeostasis and the formation and content of LDs. DDHD2 plays a role in triglyceride metabolism for normal CNS function. (PMID:29278326)
• The protective role of DDHD2 for mitochondrial integrity and provide a clue to the pathogenic mechanism of SPG54. (PMID:30038238)
• The identification of nine novel variants expands the molecular spectrum of DDHD2-related hereditary spastic paraplegia (PMID:31302745)
• Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism. (PMID:32747698)
• Genome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk. (PMID:33462483)
• Circular RNA circRUNX1 promotes papillary thyroid cancer progression and metastasis by sponging MiR-296-3p and regulating DDHD2 expression. (PMID:33479208)
• Biallelic DDHD2 mutations in patients with adult-onset complex hereditary spastic paraplegia. (PMID:37420318)
• Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5. (PMID:37837560)
• DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins. (PMID:38332048)
• Radiation-Induced Endothelial Ferroptosis Accelerates Atherosclerosis via the DDHD2-Mediated Nrf2/GPX4 Pathway. (PMID:39062593)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddhd2	ENSDARG00000076765
mus_musculus	Ddhd2	ENSMUSG00000061313
rattus_norvegicus	Ddhd2	ENSRNOG00000015501
drosophila_melanogaster	PAPLA1	FBGN0031990

Paralogs (2): DDHD1 (ENSG00000100523), SEC23IP (ENSG00000107651)

Protein

Protein identifiers

Triacylglycerol hydrolase DDHD2 — O94830 (reviewed: O94830)

Alternative names: DDHD domain-containing protein 2, KIAA0725p, Phospholipase DDHD2, SAM, WWE and DDHD domain-containing protein 1, Triglyceride hydrolase DDHD2, Triglyceride lipase

All UniProt accessions (12): O94830, E9PIF5, E9PK57, E9PKE6, E9PM60, E9PP45, E9PPH8, E9PPN2, E9PQY9, H0YE64, H0YF17, H0YF30

UniProt curated annotations — full annotation on UniProt →

Function. Diacylglycerol (DAG) and triacylglycerol (TAG) lipase required for proper lipid homeostasis in the central nervous system. It cooperates with PNPLA2/ATGL in neuronal TAG catabolism and hydrolyzes sn-1,3 DAG downstream of PNPLA2/ATGL. In vitro, it also acts as a phospholipase that hydrolyzes preferentially phosphatidic acids, including 1,2-dioleoyl-sn-phosphatidic acid, phosphatidylcholine and phosphatidylethanolamine. Specifically binds to phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4-phosphate (PI(4)P), phosphatidylinositol 5-phosphate (PI(5)P) and possibly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). May be involved in the maintenance of the endoplasmic reticulum and/or Golgi structures. May regulate the transport between Golgi apparatus and plasma membrane.

Subunit / interactions. Forms homooligomers and, to a much smaller extent, heterooligomers with DDHD1.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum-Golgi intermediate compartment. Golgi apparatus. cis-Golgi network.

Tissue specificity. Widely expressed (at protein level).

Disease relevance. Spastic paraplegia 54, autosomal recessive (SPG54) [MIM:615033] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. SPG54 patients have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions, and an abnormal lipid peak due to accumulation of neutral lipids in certain brain regions. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. SAM and DDHD domains together are required for phospholipid binding.

Similarity. Belongs to the PA-PLA1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O94830-1	1	yes
O94830-2	2

RefSeq proteins (7): NP_001157704, NP_001157706, NP_001349840, NP_001349841, NP_001349842, NP_001349843, NP_056029* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR004170	WWE_dom	Domain
IPR004177	DDHD_dom	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR057825	WWE_SEC23-DDH2	Domain
IPR058055	PA-PLA1	Family

Pfam: PF00536, PF02825, PF02862, PF23464

Catalyzed reactions (Rhea), 12 shown:

• a triacylglycerol + H2O = a diacylglycerol + a fatty acid + H(+) (RHEA:12044)
• a diacylglycerol + H2O = a monoacylglycerol + a fatty acid + H(+) (RHEA:32731)
• a 1-acylglycerol + H2O = glycerol + a fatty acid + H(+) (RHEA:34019)
• 1-(9Z-octadecenoyl)-glycerol + H2O = glycerol + (9Z)-octadecenoate + H(+) (RHEA:38487)
• 1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O = di-(9Z)-octadecenoylglycerol + (9Z)-octadecenoate + H(+) (RHEA:38575)
• 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine + H2O = (9Z-octadecenoyl)-sn-glycero-3-phosphocholine + (9Z)-octadecenoate + H(+) (RHEA:38699)
• 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine + hexadecanoate + H(+) (RHEA:38783)
• 1,3-di-(9Z-octadecenoyl)-glycerol + H2O = 1-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:39939)
• 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + hexadecanoate + H(+) (RHEA:40943)
• 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine + hexadecanoate + H(+) (RHEA:43968)
• 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + (9Z)-octadecenoate + H(+) (RHEA:45128)
• 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + hexadecanoate + H(+) (RHEA:45132)

UniProt features (23 total): mutagenesis site 6, sequence variant 4, domain 3, region of interest 3, sequence conflict 2, chain 1, splice variant 1, compositionally biased region 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94830-F1	74.70	0.36

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): 351 (nucleophile)

Post-translational modifications (1): 447

Mutagenesis-validated functional residues (6):

Position	Phenotype
103	loss of triacylglycerol hydrolase activity.
220	loss of triacylglycerol hydrolase activity.
351	abolishes phospholipase activity. loss of efficient targeting to the golgi apparatus. no effect on pi(3)p-, pi(4)p-, pi(
434	loss of phospholipid binding and of golgi/ergic localization; when associated with a-435 and a-436.
435	loss of phospholipid binding and of golgi/ergic localization; when associated with a-434 and a-436.
436	loss of phospholipid binding and of golgi/ergic localization; when associated with a-434 and a-435.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1483166	Synthesis of PA

MSigDB gene sets: 289 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GCM_MAP4K4, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_COGNITION, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_BEHAVIOR, GOBP_ASSOCIATIVE_LEARNING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_ORGANELLE_FISSION, GOBP_MITOCHONDRIAL_FISSION, GOBP_LEARNING, GOCC_COATED_VESICLE

GO Biological Process (8): mitochondrial fission (GO:0000266), locomotory behavior (GO:0007626), visual learning (GO:0008542), triglyceride catabolic process (GO:0019433), lipid droplet organization (GO:0034389), positive regulation of mitochondrial fission (GO:0090141), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042)

GO Molecular Function (6): glycerophospholipase activity (GO:0004620), triacylglycerol lipase activity (GO:0004806), metal ion binding (GO:0046872), diacylglycerol lipase activity (GO:0120516), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): cytoplasm (GO:0005737), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020), COPII-coated ER to Golgi transport vesicle (GO:0030134), centriolar satellite (GO:0034451)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
lipase activity	2
intracellular membrane-bounded organelle	2
mitochondrion organization	1
organelle fission	1
behavior	1
visual behavior	1
associative learning	1
triglyceride metabolic process	1
acylglycerol catabolic process	1
organelle organization	1
mitochondrial fission	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
primary metabolic process	1
lipid metabolic process	1
catabolic process	1
phospholipase activity	1
carboxylic ester hydrolase activity	1
cation binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
endomembrane system	1
coated vesicle	1
centrosome	1

Protein interactions and networks

STRING

1060 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDHD2	PNPLA6	Q8IY17	681
DDHD2	ERLIN2	O94905	657
DDHD2	CYP2U1	Q7Z449	629
DDHD2	GBA2	Q9HCG7	621
DDHD2	PLPP5	Q8NEB5	621
DDHD2	SPG21	Q9NZD8	620
DDHD2	FA2H	Q7L5A8	617
DDHD2	SPAST	Q9UBP0	614
DDHD2	SPG11	Q96JI7	613
DDHD2	PLPBP	O94903	612
DDHD2	AP5Z1	O43299	604
DDHD2	ZFYVE26	Q68DK2	599
DDHD2	LSM1	O15116	584
DDHD2	REEP1	Q9H902	583
DDHD2	LIPH	Q8WWY8	582

IntAct

30 interactions, top by confidence:

A	B	Type	Score
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
C2orf68	PIR	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
TGM4	DDHD2	psi-mi:“MI:0914”(association)	0.530
BLVRA	DDHD2	psi-mi:“MI:0914”(association)	0.530
DDHD2	CHI3L1	psi-mi:“MI:0914”(association)	0.530
IFIH1	DDHD2	psi-mi:“MI:0914”(association)	0.350
IFIH1	FAM168B	psi-mi:“MI:0914”(association)	0.350
AARSD1	APAF1	psi-mi:“MI:0914”(association)	0.350
RAPGEF5	DDHD2	psi-mi:“MI:0914”(association)	0.350
RCCD1	ZNF609	psi-mi:“MI:0914”(association)	0.350
LRRC8E	TBC1D4	psi-mi:“MI:0914”(association)	0.350
rep	B4GALT3	psi-mi:“MI:0914”(association)	0.350
PCDH10	TMEM223	psi-mi:“MI:0914”(association)	0.350
SIDT2	KLRG2	psi-mi:“MI:0914”(association)	0.350
AARSD1	MAP3K7	psi-mi:“MI:0914”(association)	0.350
DDHD2	CP	psi-mi:“MI:0914”(association)	0.350
SLC49A4	AP3B1	psi-mi:“MI:0914”(association)	0.350
COPB1	DDHD2	psi-mi:“MI:0403”(colocalization)	0.270
GOLGA2	DDHD2	psi-mi:“MI:0403”(colocalization)	0.270
DDHD2	MTNR1A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (63): DDHD2 (Affinity Capture-MS), SEC23IP (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), EEF1A2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), SEC23IP (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), DDHD2 (Affinity Capture-MS), DDHD2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K344, D3ZGS3, F1M386, F1MSG6, F1PBJ0, G5EF51, O00329, O02697, O35242, O35904, O70481, O88763, O94830, P32871, P42336, P42337, P42338, P42339, P42347, P42348, P48736, P50520, P54676, P70600, Q01968, Q14289, Q14BI7, Q16JS8, Q3MHU3, Q3UYK3, Q4KWH5, Q4KWH8, Q5D891, Q5ZI89, Q6AZN6, Q6GQ76, Q6NVF0, Q6PF93, Q7Z392, Q80Y98

Diamond homologs: O94830, Q495M9, Q6NZC7, Q80T11, Q80Y98, Q80YA3, Q8K3X6, Q8N8V4, Q9Y6Y8, O14593, Q3KP44, Q8BLD6, Q9Z205, O00562, O35954, P43125, Q12204, Q3UHE1, Q5U2N3, Q6ZPQ6, Q9BZ71, Q9BZ72, G5EEM9, O46606, Q8NEL9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
DDHD2	“down-regulates quantity”	“phosphatidic acid”	“chemical modification”
DDHD2	“up-regulates quantity”	“long-chain fatty acid anion”	“chemical modification”
DDHD2	“up-regulates quantity”	“1-acyl-sn-glycerol 3-phosphate”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	16
Uncertain significance	214
Likely benign	127
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
101083	NM_015214.3(DDHD2):c.1057+5C>G	Pathogenic
1076234	NC_000008.10:g.(?38095036)(38095747_?)del	Pathogenic
2067256	NM_015214.3(DDHD2):c.196C>T (p.Gln66Ter)	Pathogenic
2202619	NM_015214.3(DDHD2):c.815G>A (p.Trp272Ter)	Pathogenic
2275961	NM_015214.3(DDHD2):c.1877C>G (p.Ser626Ter)	Pathogenic
2694153	NM_015214.3(DDHD2):c.453_454del (p.Lys152fs)	Pathogenic
3068415	NM_015214.3(DDHD2):c.819_820del (p.His273fs)	Pathogenic
3665854	NM_015214.3(DDHD2):c.344G>A (p.Trp115Ter)	Pathogenic
39676	NM_015214.3(DDHD2):c.1803dup (p.Thr602fs)	Pathogenic
39677	NM_015214.3(DDHD2):c.2057del (p.Glu686fs)	Pathogenic
39680	NM_015214.3(DDHD2):c.1546C>T (p.Arg516Ter)	Pathogenic
452548	NM_015214.3(DDHD2):c.985C>T (p.Arg329Ter)	Pathogenic
4738058	NM_015214.3(DDHD2):c.1240_1243del (p.Glu414fs)	Pathogenic
503722	NM_015214.3(DDHD2):c.1386dup (p.Ile463fs)	Pathogenic
523988	NM_015214.3(DDHD2):c.94_101dup (p.Ser35fs)	Pathogenic
540287	NM_015214.3(DDHD2):c.1803del (p.Phe601fs)	Pathogenic
634496	NM_015214.3(DDHD2):c.694C>T (p.Arg232Ter)	Pathogenic
638323	NM_015214.3(DDHD2):c.334C>T (p.Arg112Ter)	Pathogenic
653596	NM_015214.3(DDHD2):c.420C>A (p.Tyr140Ter)	Pathogenic
655242	NC_000008.11:g.(?38242230)(38247855_?)del	Pathogenic
988995	NM_015214.3(DDHD2):c.1529G>A (p.Gly510Glu)	Pathogenic
988996	NC_000008.10:g.(?38090513)(38117639_?)del	Pathogenic
1202525	NM_015214.3(DDHD2):c.1264C>T (p.Arg422Ter)	Likely pathogenic
1686646	NM_015214.3(DDHD2):c.400C>T (p.Gln134Ter)	Likely pathogenic
1696332	NM_015214.3(DDHD2):c.1126-2A>G	Likely pathogenic
1709490	NM_015214.3(DDHD2):c.1217_1218del (p.Ile405_Phe406insTer)	Likely pathogenic
183317	NM_015214.2(DDHD2):c.1249_1891del	Likely pathogenic
2025715	NM_015214.3(DDHD2):c.1617+1G>T	Likely pathogenic
2439662	NM_015214.3(DDHD2):c.1901delinsTCTGTGGCAGTTAA (p.Thr634delinsIleCysGlySerTer)	Likely pathogenic
3068647	NM_015214.3(DDHD2):c.1887_1890dup (p.Asp631Ter)	Likely pathogenic

SpliceAI

4345 predictions. Top by Δscore:

Variant	Effect	Δscore
8:38234382:A:AG	acceptor_gain	1.0000
8:38234383:A:G	acceptor_gain	1.0000
8:38234388:T:TA	acceptor_gain	1.0000
8:38237532:TTTAA:T	acceptor_loss	1.0000
8:38237533:TTAAG:T	acceptor_loss	1.0000
8:38237534:TAA:T	acceptor_loss	1.0000
8:38237535:A:AG	acceptor_gain	1.0000
8:38237535:AAG:A	acceptor_gain	1.0000
8:38237536:A:G	acceptor_gain	1.0000
8:38237537:G:GT	acceptor_loss	1.0000
8:38237623:CAAAG:C	donor_loss	1.0000
8:38237624:AAAG:A	donor_loss	1.0000
8:38237625:AAGGT:A	donor_loss	1.0000
8:38237626:AGGTA:A	donor_loss	1.0000
8:38237627:GGTAA:G	donor_loss	1.0000
8:38237629:T:A	donor_loss	1.0000
8:38238087:A:G	acceptor_gain	1.0000
8:38238088:GCTT:G	acceptor_gain	1.0000
8:38240360:GTGTG:G	donor_gain	1.0000
8:38242248:A:AG	acceptor_gain	1.0000
8:38242249:G:GG	acceptor_gain	1.0000
8:38242249:GTT:G	acceptor_gain	1.0000
8:38242249:GTTA:G	acceptor_gain	1.0000
8:38242381:GATGT:G	donor_gain	1.0000
8:38242384:GT:G	donor_gain	1.0000
8:38242386:G:GG	donor_gain	1.0000
8:38245737:TTCA:T	acceptor_loss	1.0000
8:38245740:A:AG	acceptor_gain	1.0000
8:38245741:G:GA	acceptor_gain	1.0000
8:38245741:GA:G	acceptor_gain	1.0000

AlphaMissense

4697 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:38233124:T:A	W44R	1.000
8:38233124:T:C	W44R	1.000
8:38233160:T:A	W56R	1.000
8:38233160:T:C	W56R	1.000
8:38234516:T:A	W115R	1.000
8:38234516:T:C	W115R	1.000
8:38238174:G:C	R196T	1.000
8:38238175:A:C	R196S	1.000
8:38238175:A:T	R196S	1.000
8:38240302:T:A	V217D	1.000
8:38240316:G:A	G222R	1.000
8:38240316:G:C	G222R	1.000
8:38240316:G:T	G222W	1.000
8:38240317:G:A	G222E	1.000
8:38240317:G:T	G222V	1.000
8:38240322:G:A	G224R	1.000
8:38240322:G:C	G224R	1.000
8:38240323:G:A	G224E	1.000
8:38240347:G:C	R232P	1.000
8:38242262:G:C	R242P	1.000
8:38242346:T:A	V270D	1.000
8:38242351:T:A	W272R	1.000
8:38242351:T:C	W272R	1.000
8:38242353:G:C	W272C	1.000
8:38242353:G:T	W272C	1.000
8:38245783:G:C	R297T	1.000
8:38245783:G:T	R297M	1.000
8:38245784:G:C	R297S	1.000
8:38245784:G:T	R297S	1.000
8:38245809:G:C	D306H	1.000

dbSNP variants (sampled 300 via entrez): RS1000017733 (8:38241205 G>A), RS1000058844 (8:38270782 A>G), RS1000126308 (8:38251148 G>A), RS1000251668 (8:38231358 C>A), RS1000311811 (8:38244889 A>T), RS1000326593 (8:38256081 A>C,T), RS1000330798 (8:38248717 T>C,G), RS1000366334 (8:38270423 A>C), RS1000412911 (8:38237697 C>T), RS1000431558 (8:38270684 A>C,T), RS1000466168 (8:38249928 T>A,C), RS1000538356 (8:38242326 G>A,T), RS1000583878 (8:38255766 T>C), RS1000685286 (8:38244754 C>T), RS1000713255 (8:38235949 T>C)

Disease associations

OMIM: gene MIM:615003 | disease phenotypes: MIM:615033, MIM:610189, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 54	Definitive	Autosomal recessive

Mondo (5): hereditary spastic paraplegia 54 (MONDO:0014018), Senior-Loken syndrome 6 (MONDO:0012433), hereditary spastic paraplegia (MONDO:0019064), obesity disorder (MONDO:0011122), generalized epilepsy (MONDO:0100574)

Orphanet (5): Autosomal recessive spastic paraplegia type 54 (Orphanet:320380), Senior-Loken syndrome (Orphanet:3156), Hereditary spastic paraplegia (Orphanet:685), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000218	High palate
HP:0000338	Hypomimic face
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000609	Optic nerve hypoplasia
HP:0001249	Intellectual disability
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002015	Dysphagia
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002064	Spastic gait
HP:0002079	Hypoplasia of the corpus callosum
HP:0002607	Bowel incontinence
HP:0003396	Syringomyelia
HP:0003487	Babinski sign
HP:0003676	Progressive
HP:0004322	Short stature
HP:0006970	Periventricular leukomalacia
HP:0006986	Upper limb spasticity
HP:0007340	Lower limb muscle weakness
HP:0007766	Optic disc hypoplasia
HP:0008366	Foot joint contracture
HP:0008959	Distal upper limb muscle weakness

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004521_242	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST004946_16	Schizophrenia	1.000000e-11
GCST006803_65	Schizophrenia	6.000000e-10

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C565708	Senior-Loken Syndrome 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5723581 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.89	IC50	1.3	nM	CHEMBL5723376
8.44	IC50	3.6	nM	CHEMBL5723376

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
beryllium sulfate	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
arsenic disulfide	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	decreases expression	1
Flavoring Agents	affects cotreatment, increases expression	1
Glycerol	affects cotreatment, increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Nicotine	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
Antirheumatic Agents	increases expression	1
Propylene Glycol	affects cotreatment, increases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5723257	Functional	Affinity Biochemical interaction: (Gel-based competitive activity-based protein profiling with HT-01 probe and membranes) EUB0002612a DDHD2	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1VF	HAP1 DDHD2 (-) 2	Cancer cell line	Male
CVCL_XN18	HAP1 DDHD2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin