DDHD1

Summary

DDHD1 (DDHD domain containing 1, HGNC:19714) is a protein-coding gene on chromosome 14q22.1, encoding Phospholipase DDHD1 (Q8NEL9). Phospholipase A1 (PLA1) that hydrolyzes ester bonds at the sn-1 position of glycerophospholipids producing a free fatty acid and a lysophospholipid.

This gene is a member of the intracellular phospholipase A1 gene family. The protein encoded by this gene preferentially hydrolyzes phosphatidic acid. It is a cytosolic protein with some mitochondrial localization, and is thought to be involved in the regulation of mitochondrial dynamics. Overexpression of this gene causes fragmentation of the tubular structures in mitochondria, while depletion of the gene results in mitochondrial tubule elongation. Deletion of this gene in male mice caused fertility defects, resulting from disruption in the organization of the mitochondria during spermiogenesis. In humans, mutations in this gene have been associated with hereditary spastic paraplegia (HSP), also known as Strumpell-Lorrain disease, or, familial spastic paraparesis (FSP). This inherited disorder is characterized by progressive weakness and spasticity of the legs. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 80821 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 593 total — 24 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 21
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001160148

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19714
Approved symbol	DDHD1
Name	DDHD domain containing 1
Location	14q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1705, PA-PLA1, iPLA1alpha, PAPLA1, iPLA1α
Ensembl gene	ENSG00000100523
Ensembl biotype	protein_coding
OMIM	614603
Entrez	80821

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 14 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000323669, ENST00000357758, ENST00000395606, ENST00000553406, ENST00000555400, ENST00000555621, ENST00000556027, ENST00000556910, ENST00000557445, ENST00000673822, ENST00000673827, ENST00000673930, ENST00000674014, ENST00000674152, ENST00000907172, ENST00000907173, ENST00000907174, ENST00000907175, ENST00000907176, ENST00000907177, ENST00000921203

RefSeq mRNA: 3 — MANE Select: NM_001160148 NM_001160147, NM_001160148, NM_030637

CCDS: CCDS53895, CCDS53896, CCDS9714

Canonical transcript exons

ENST00000673822 — 13 exons

Exon	Start	End
ENSE00000940848	53093316	53093444
ENSE00001164786	53051844	53051927
ENSE00001245384	53091785	53091932
ENSE00001933018	53152261	53153323
ENSE00003525500	53073741	53073847
ENSE00003577834	53061126	53061201
ENSE00003597526	53054438	53054629
ENSE00003610979	53058477	53058626
ENSE00003617089	53062943	53063205
ENSE00003620868	53072597	53072703
ENSE00003648423	53055660	53055912
ENSE00003676572	53103683	53103856
ENSE00003897472	53036755	53046949

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 93.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.5299 / max 165.5949, expressed in 1733 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143281	9.9175	1731
143280	0.6125	219

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	93.17	gold quality
corpus callosum	UBERON:0002336	92.10	gold quality
subthalamic nucleus	UBERON:0001906	91.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.35	gold quality
inferior vagus X ganglion	UBERON:0005363	91.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.55	gold quality
superior vestibular nucleus	UBERON:0007227	90.45	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.35	gold quality
lateral globus pallidus	UBERON:0002476	90.20	gold quality
medulla oblongata	UBERON:0001896	89.60	gold quality
postcentral gyrus	UBERON:0002581	89.23	gold quality
parietal lobe	UBERON:0001872	89.14	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.91	gold quality
calcaneal tendon	UBERON:0003701	88.76	gold quality
secondary oocyte	CL:0000655	88.54	gold quality
decidua	UBERON:0002450	88.48	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.35	gold quality
substantia nigra pars compacta	UBERON:0001965	88.31	gold quality
testis	UBERON:0000473	87.98	gold quality
pons	UBERON:0000988	87.82	gold quality
lateral nuclear group of thalamus	UBERON:0002736	87.79	gold quality
right testis	UBERON:0004534	87.41	gold quality
left testis	UBERON:0004533	87.35	gold quality
superior frontal gyrus	UBERON:0002661	86.98	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.91	gold quality
bone marrow cell	CL:0002092	86.61	gold quality
occipital lobe	UBERON:0002021	86.42	gold quality
middle temporal gyrus	UBERON:0002771	86.05	gold quality
stromal cell of endometrium	CL:0002255	85.90	gold quality
entorhinal cortex	UBERON:0002728	85.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.08
E-MTAB-7381	no	2793.49

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

386 targeting DDHD1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4682	100.00	68.89	1258
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• DDHD1-LPI-GPR55 axis to be involved in functions in the brain. (PMID:20359546)
• a possible mechanism of PA regulation of the mitochondrial membrane and demonstrate an in vivo function of PA-PLA1 in the organization of mitochondria during spermiogenesis. (PMID:24599962)
• Two novel heterozygous mutations in DDHD1 were found in the affected members of one family, with clinical features overlapping the SPG28 subtype. (PMID:24989667)
• the novel mutation in DDHD1 is the causative variant for the SPG28 patient that is the first record of the disease in Japanese population. (PMID:27216551)
• A novel homozygous mutation in DDHD1 was identified in a patient with hereditary spastic paraplegia, retinal dystrophy and a pattern of neurodegeneration with brain iron accumulation. (PMID:28818478)
• Expression of Lysophosphatidylinositol Signaling-relevant Molecules in Colorectal Cancer. (PMID:33952459)
• Phosphorylation of human phospholipase A1 DDHD1 at newly identified phosphosites affects its subcellular localization. (PMID:34089703)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddhd1b	ENSDARG00000037042
danio_rerio	ddhd1a	ENSDARG00000086808
mus_musculus	Ddhd1	ENSMUSG00000037697
rattus_norvegicus	Ddhd1	ENSRNOG00000009481
caenorhabditis_elegans		WBGENE00019747

Paralogs (2): DDHD2 (ENSG00000085788), SEC23IP (ENSG00000107651)

Protein

Protein identifiers

Phospholipase DDHD1 — Q8NEL9 (reviewed: Q8NEL9)

Alternative names: DDHD domain-containing protein 1, Phosphatidic acid-preferring phospholipase A1 homolog, Phospholipid sn-1 acylhydrolase

All UniProt accessions (6): Q8NEL9, A0A669KAW5, A0A669KB51, A0A669KB64, A0A6E1W401, G3V2P6

UniProt curated annotations — full annotation on UniProt →

Function. Phospholipase A1 (PLA1) that hydrolyzes ester bonds at the sn-1 position of glycerophospholipids producing a free fatty acid and a lysophospholipid. Prefers phosphatidate (1,2-diacyl-sn-glycero-3-phosphate, PA) as substrate in vitro, but can efficiently hydrolyze phosphatidylinositol (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol), PI), as well as a range of other glycerophospholipid substrates such as phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine, PC), phosphatidylethanolamine (1,2-diacyl-sn-glycero-3-phosphoethanolamine, PE), phosphatidylserine (1,2-diacyl-sn-glycero-3-phospho-L-serine, PS) and phosphatidylglycerol (1,2-diacyl-sn-glycero-3-phospho-(1’-sn-glycerol), PG). Involved in the regulation of the endogenous content of polyunsaturated PI and PS lipids in the nervous system. Changes in these lipids extend to downstream metabolic products like PI phosphates PIP and PIP2, which play fundamental roles in cell biology. Regulates mitochondrial morphology. These dynamic changes may be due to PA hydrolysis at the mitochondrial surface. May play a regulatory role in spermatogenesis or sperm function.

Subunit / interactions. Forms homooligomers and, to a much smaller extent, heterooligomers with DDHD2.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in testis. Also expressed in brain, spleen and lung. Only expressed in cerebellum in fetal brain.

Disease relevance. Spastic paraplegia 28, autosomal recessive (SPG28) [MIM:609340] 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. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. Some SPG28 patients also have distal sensory impairment. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Phosphatidate (1,2-diacyl-sn-glycero-3-phosphate, PA) can positively regulate phospholipase A1 activity.

Pathway. Phospholipid metabolism; phosphatidylinositol metabolism.

Similarity. Belongs to the PA-PLA1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NEL9-1	1	yes
Q8NEL9-2	2
Q8NEL9-3	3
Q8NEL9-4	4

RefSeq proteins (3): NP_001153619, NP_001153620, NP_085140 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004177	DDHD_dom	Domain
IPR058055	PA-PLA1	Family

Pfam: PF02862

Enzyme classification (BRENDA):

• EC 3.1.1.118 — phospholipid sn-1 acylhydrolase (BRENDA: 6 organisms, 43 substrates, 4 inhibitors, 0 Km, 0 kcat entries)
• EC 3.1.1.32 — phospholipase A1 (BRENDA: 55 organisms, 221 substrates, 99 inhibitors, 14 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHATIDYLCHOLINE	0.11–4	4
1-PALMITOYL-2-ARACHIDONOYLGLYCEROPHOSPHOCHOLINE	0.5	1
DIACYL-SN-GLYCERO-3-PHOSPHORYLCHOLINE	0.6	1
DIACYL-SN-GLYCERO-3-PHOSPHORYLETHANOLAMINE	0.92	1
DIACYL-SN-GLYCERO-3-PHOSPHORYLSERINE	1.19	1
PHOSPHATIDIC ACID	2.38	1
PHOSPHATIDYLGLYCEROL	0.0003	1
SOYBEAN LECITHIN	18.53	1
TRIACYLGLYCEROL	1.53	1
HIGH-DENSITY LIPOPROTEIN	—	0

Catalyzed reactions (Rhea), 12 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 2-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:18689)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + H2O = a 2-acyl-sn-glycero-3-phospho-D-myo-inositol + a fatty acid + H(+) (RHEA:35263)
• 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-phosphate + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + hexadecanoate + H(+) (RHEA:40943)
• a 1,2-diacyl-sn-glycero-3-phospho-L-serine + H2O = a 2-acyl-sn-glycero-3-phospho-L-serine + a fatty acid + H(+) (RHEA:42212)
• 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)
• a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + H2O = a 2-acyl-sn-glycero-3-phosphoethanolamine + a fatty acid + H(+) (RHEA:44408)
• a 1,2-diacyl-sn-glycero-3-phosphate + H2O = a 2-acyl-sn-glycerol 3-phosphate + a fatty acid + H(+) (RHEA:44648)
• 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + (9Z)-octadecenoate + H(+) (RHEA:45128)
• 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol) + H2O = 2-hexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol) + hexadecanoate + H(+) (RHEA:66708)
• a 1,2-diacyl-sn-glycero-3-phospho-(1’-sn-glycerol) + H2O = 2-acyl-sn-glycero-3-phospho-(1’-sn-glycerol) + a fatty acid + H(+) (RHEA:67428)
• 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phospho-(1D-myo-inositol) + H2O = 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phospho-(1D-myo-inositol) + octadecanoate + H(+) (RHEA:73967)

UniProt features (26 total): mutagenesis site 6, region of interest 5, compositionally biased region 4, modified residue 3, splice variant 3, sequence conflict 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEL9-F1	67.11	0.32

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): 537

Post-translational modifications (3): 8, 11, 723

Mutagenesis-validated functional residues (6):

Position	Phenotype
590	no effect on homooligomer formation; when associated with s-593.
593	no effect on homooligomer formation; when associated with s-590.
662	markedly decreased enzymatic activity.
848	markedly decreased enzymatic activity.
867	markedly decreased enzymatic activity.
875	no effect on enzymatic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1483166	Synthesis of PA

MSigDB gene sets: 272 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, MYOGENIN_Q6, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_ORGANELLE_FISSION, GOBP_MITOCHONDRIAL_FISSION, GOBP_REGULATION_OF_MITOCHONDRIAL_FISSION, LIAO_METASTASIS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS

GO Biological Process (3): phosphatidylinositol metabolic process (GO:0046488), positive regulation of mitochondrial fission (GO:0090141), lipid metabolic process (GO:0006629)

GO Molecular Function (5): glycerophospholipase activity (GO:0004620), glycerophospholipid phospholipase A1 activity (GO:0008970), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

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	2
phosphorus metabolic process	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
phospholipase activity	1
A1-type glycerophospholipase activity	1
cation binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1146 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDHD1	TECPR2	O15040	687
DDHD1	C19orf12	Q9NSK7	656
DDHD1	PNPLA6	Q8IY17	646
DDHD1	PLA2G6	O60733	634
DDHD1	POU2F3	Q9UKI9	621
DDHD1	GBA2	Q9HCG7	619
DDHD1	REEP1	Q9H902	609
DDHD1	CYP2U1	Q7Z449	603
DDHD1	AP4S1	Q9Y587	598
DDHD1	AP5Z1	O43299	595
DDHD1	SPG11	Q96JI7	581
DDHD1	SPAST	Q9UBP0	553
DDHD1	AP4B1	Q9Y6B7	549
DDHD1	FA2H	Q7L5A8	544
DDHD1	SPG7	Q9UQ90	537

IntAct

28 interactions, top by confidence:

A	B	Type	Score
SOST	LRP6	psi-mi:“MI:0914”(association)	0.890
PDIK1L	CTDSPL2	psi-mi:“MI:0914”(association)	0.840
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
HMCES	HSPA8	psi-mi:“MI:0914”(association)	0.640
SGO1	USP12	psi-mi:“MI:0914”(association)	0.530
DYNLL1	SHMT2	psi-mi:“MI:0914”(association)	0.510
DYNLL2	SHMT2	psi-mi:“MI:0914”(association)	0.510
DDHD1	AXIN1	psi-mi:“MI:0915”(physical association)	0.400
DDHD1	BANF1	psi-mi:“MI:0915”(physical association)	0.400
P		psi-mi:“MI:0914”(association)	0.350
DDHD1	USP9Y	psi-mi:“MI:0914”(association)	0.350
DDHD1	PYGM	psi-mi:“MI:0914”(association)	0.350
GOLGA2	UPK2	psi-mi:“MI:0914”(association)	0.350
KPNA2	TAF4	psi-mi:“MI:0914”(association)	0.350
MICB	LGALS8	psi-mi:“MI:0914”(association)	0.350
MLH1	GLI2	psi-mi:“MI:0914”(association)	0.350
TAF7L	KLRG2	psi-mi:“MI:0914”(association)	0.350
DYNLL1	DDHD1	psi-mi:“MI:0915”(physical association)	0.000
IFFO1	DDHD1	psi-mi:“MI:0915”(physical association)	0.000
COBLL1	DDHD1	psi-mi:“MI:0915”(physical association)	0.000
AMOTL1	DDHD1	psi-mi:“MI:0915”(physical association)	0.000
DYNLL2	DDHD1	psi-mi:“MI:0915”(physical association)	0.000
DDHD1	CDADC1	psi-mi:“MI:0915”(physical association)	0.000
DDHD1	SCML1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (45): DDHD1 (Affinity Capture-MS), DDHD1 (Affinity Capture-MS), DDHD1 (Affinity Capture-MS), DDHD1 (Affinity Capture-MS), DDHD1 (Affinity Capture-MS), CDADC1 (Affinity Capture-MS), DDHD1 (Affinity Capture-MS), SCML1 (Affinity Capture-MS), DDHD1 (Affinity Capture-RNA), DDHD1 (Affinity Capture-MS), DDHD1 (Affinity Capture-RNA), ZBTB24 (Two-hybrid), CR1L (Two-hybrid), DDHD1 (Proximity Label-MS), DDHD1 (Proximity Label-MS)

ESM2 similar proteins: A1A5G2, A2AFR3, A7MBL8, B9EJ86, E1C1R4, E1C3P4, F1LXF1, O94806, O94967, P0C6S7, P0CAX5, P11274, P22682, Q0V9G5, Q14161, Q14CM0, Q15139, Q16513, Q1RMU2, Q3KR37, Q3LAC4, Q3UGM2, Q5RED8, Q5T6S3, Q5U252, Q62101, Q66H62, Q6DFZ1, Q6P5G6, Q6PAJ1, Q70Z35, Q7Z6G8, Q80TI0, Q80TQ2, Q80YA9, Q8BIZ1, Q8BWW9, Q8BY87, Q8K1Y2, Q8NEL9

Diamond homologs: G5EEM9, O00562, O35954, O46606, P43125, Q5U2N3, Q6ZPQ6, Q80YA3, Q8NEL9, P16446, P48738, P48739, P53810, P53811, P53812, Q00169, Q28CA0, Q2HJ54, Q3UHE1, Q54D93, Q54VC7, Q5R6F0, Q6NZC7, Q8K4R4, Q8W5R2, Q9BZ71, Q9BZ72, Q9NCL7, Q9NCL8, Q9TR36, Q9U9P7, Q9UKF7, Q8ET41, Q12204, O94830, Q80Y98

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
DDHD1	“down-regulates quantity”	“phosphatidic acid”	“chemical modification”
DDHD1	“up-regulates quantity”	“long-chain fatty acid anion”	“chemical modification”
DDHD1	“up-regulates quantity”	“1-acyl-sn-glycerol 3-phosphate”	“chemical modification”
MAPK1	unknown	DDHD1	phosphorylation
CSNK2A1	“down-regulates activity”	DDHD1	phosphorylation
PPP2CA	“up-regulates activity”	DDHD1	dephosphorylation
PPP2CA	unknown	DDHD1	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	5
Uncertain significance	288
Likely benign	191
Benign	48

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1071245	NM_001160148.2(DDHD1):c.5dup (p.Asn2fs)	Pathogenic
1120268	NM_001160148.2(DDHD1):c.1637_1638dup (p.Met547Ter)	Pathogenic
2015090	NM_001160148.2(DDHD1):c.1371G>A (p.Trp457Ter)	Pathogenic
2020629	NM_001160148.2(DDHD1):c.184del (p.Glu62fs)	Pathogenic
2099568	NM_001160148.2(DDHD1):c.456_463dup (p.His155fs)	Pathogenic
2158823	NM_001160148.2(DDHD1):c.1729C>T (p.Arg577Ter)	Pathogenic
2644245	NM_001160148.2(DDHD1):c.456_463del (p.Ala153fs)	Pathogenic
2699071	NM_001160148.2(DDHD1):c.731del (p.His244fs)	Pathogenic
2815864	NM_001160148.2(DDHD1):c.1996del (p.Tyr666fs)	Pathogenic
3338263	NM_001160148.2(DDHD1):c.1824dup (p.Pro609fs)	Pathogenic
3706662	NM_001160148.2(DDHD1):c.1473del (p.Met491fs)	Pathogenic
3720709	NM_001160148.2(DDHD1):c.344dup (p.Leu115fs)	Pathogenic
3721963	NM_001160148.2(DDHD1):c.702_708del (p.Cys235fs)	Pathogenic
39671	NM_001160148.2(DDHD1):c.1766G>A (p.Arg589Gln)	Pathogenic
39672	NM_001160148.2(DDHD1):c.1874del (p.Pro624_Leu625insTer)	Pathogenic
39673	NM_001160148.2(DDHD1):c.1249C>T (p.Gln417Ter)	Pathogenic
39674	NM_001160148.2(DDHD1):c.2522-1G>T	Pathogenic
4810778	NM_001160148.2(DDHD1):c.259G>T (p.Glu87Ter)	Pathogenic
951954	NM_001160148.2(DDHD1):c.1044dup (p.Val349fs)	Pathogenic
954039	NM_001160148.2(DDHD1):c.971del (p.Asn324fs)	Pathogenic
986847	NM_001160148.2(DDHD1):c.1031T>A (p.Leu344Ter)	Pathogenic
989056	NM_001160148.2(DDHD1):c.246del (p.Cys83fs)	Pathogenic
989057	NM_001160148.2(DDHD1):c.395dup (p.Gly133fs)	Pathogenic
989058	NM_001160148.2(DDHD1):c.510G>A (p.Trp170Ter)	Pathogenic
1299394	NM_001160148.2(DDHD1):c.1842+1G>A	Likely pathogenic
2503254	NM_001160148.2(DDHD1):c.1755_1758delinsTAACA (p.Thr586fs)	Likely pathogenic
3779563	NM_001160148.2(DDHD1):c.1762C>T (p.Arg588Ter)	Likely pathogenic
3899853	NM_001160148.2(DDHD1):c.1993_2437+5del	Likely pathogenic
800955	NM_001160148.2(DDHD1):c.2444G>A (p.Arg815Lys)	Likely pathogenic

SpliceAI

2512 predictions. Top by Δscore:

Variant	Effect	Δscore
14:53046945:CTCCA:C	acceptor_gain	1.0000
14:53046947:CCA:C	acceptor_gain	1.0000
14:53046948:CAC:C	acceptor_gain	1.0000
14:53046950:C:CC	acceptor_gain	1.0000
14:53058549:T:TA	donor_gain	1.0000
14:53061120:CCTTA:C	donor_loss	1.0000
14:53061121:CTTA:C	donor_loss	1.0000
14:53061122:TTA:T	donor_loss	1.0000
14:53061123:TACC:T	donor_loss	1.0000
14:53061124:A:AG	donor_loss	1.0000
14:53061202:C:CC	acceptor_gain	1.0000
14:53062942:CCGT:C	donor_gain	1.0000
14:53063150:C:CT	acceptor_gain	1.0000
14:53063150:C:T	acceptor_gain	1.0000
14:53063151:G:T	acceptor_gain	1.0000
14:53063202:CTAG:C	acceptor_gain	1.0000
14:53063206:C:CC	acceptor_gain	1.0000
14:53072589:ACACT:A	donor_loss	1.0000
14:53072592:CT:C	donor_loss	1.0000
14:53072593:TTACT:T	donor_loss	1.0000
14:53072595:A:AC	donor_gain	1.0000
14:53072596:C:CT	donor_gain	1.0000
14:53072596:CTT:C	donor_gain	1.0000
14:53072700:GTGT:G	acceptor_gain	1.0000
14:53072701:TGT:T	acceptor_gain	1.0000
14:53072701:TGTC:T	acceptor_loss	1.0000
14:53072702:GTC:G	acceptor_loss	1.0000
14:53072703:TCTA:T	acceptor_loss	1.0000
14:53072704:C:CC	acceptor_gain	1.0000
14:53072704:C:CG	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000043073 (14:53135059 T>C), RS1000096646 (14:53097654 G>C), RS1000099618 (14:53072143 A>C), RS1000100708 (14:53120753 A>G), RS1000167222 (14:53059235 T>C), RS1000223763 (14:53150096 T>C), RS1000237173 (14:53039587 G>T), RS1000241562 (14:53142992 A>G), RS1000265330 (14:53104645 T>C), RS1000311098 (14:53152902 T>A,G), RS1000318919 (14:53077326 C>A), RS1000325617 (14:53076132 C>T), RS1000340714 (14:53104237 C>T), RS1000344190 (14:53153239 G>A,T), RS1000386285 (14:53071373 A>G)

Disease associations

OMIM: gene MIM:614603 | disease phenotypes: MIM:609340, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 28	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary spastic paraplegia	Definitive	AR

Mondo (2): hereditary spastic paraplegia 28 (MONDO:0012256), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (2): Autosomal recessive spastic paraplegia type 28 (Orphanet:101008), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001258	Spastic paraplegia
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002061	Lower limb spasticity
HP:0002063	Rigidity
HP:0002064	Spastic gait
HP:0002172	Postural instability
HP:0002317	Unsteady gait
HP:0002650	Scoliosis
HP:0002936	Distal sensory impairment
HP:0003477	Peripheral axonal neuropathy
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0006944	Abolished vibration sense
HP:0007021	Pain insensitivity
HP:0007340	Lower limb muscle weakness
HP:0010830	Impaired tactile sensation

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001942_15	Prostate cancer	2.000000e-14
GCST002764_13	Optic cup area	7.000000e-07
GCST002764_7	Optic cup area	5.000000e-09
GCST003445_5	Response to cyclophosphamide in systemic lupus erythematosus with lupus nephritis	2.000000e-06
GCST003445_7	Response to cyclophosphamide in systemic lupus erythematosus with lupus nephritis	2.000000e-06
GCST003989_8	Chin dimples	6.000000e-32
GCST004137_24	Optic cup area	6.000000e-08
GCST004137_40	Optic cup area	1.000000e-09
GCST006482_24	Lung function (FEV1/FVC)	4.000000e-08
GCST006482_25	Lung function (FEV1/FVC)	2.000000e-07
GCST009404_6	Optic cup area	2.000000e-08
GCST009723_52	Vertical cup-disc ratio (adjusted for vertical disc diameter)	8.000000e-11
GCST90002401_73	Platelet distribution width	5.000000e-11
GCST90002402_181	Platelet count	4.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0006939	cup-to-disc ratio measurement
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

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
C563732	Spastic Paraplegia 28, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17126068	Dosage	3	warfarin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	9
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	decreases expression	1
Irinotecan	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Succimer	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Pesticides	affects methylation	1
Plant Extracts	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury
NCT05613114	Not specified	COMPLETED	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia
NCT05767268	Not specified	COMPLETED	Assessment of the Psychophysical State During Rehabilitation Treatment With Lokomat
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies
NCT06573866	Not specified	RECRUITING	Enhancement of Quality of Work And Life
NCT06680063	Not specified	COMPLETED	Correlation Between Clinical Assessment and Neurophysiological Assessment in Spinal Cord Injury