COQ4

Summary

COQ4 (coenzyme Q4, HGNC:19693) is a protein-coding gene on chromosome 9q34.11, encoding Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (Q9Y3A0). Lyase that catalyzes the C1-decarboxylation of 4-hydroxy-3-methoxy-5-(all-trans-decaprenyl)benzoic acid into 2-methoxy-6-(all-trans-decaprenyl)phenol during ubiquinone biosynthesis. It is a selective cancer dependency (DepMap: 67.1% of cell lines).

This gene encodes a component of the coenzyme Q biosynthesis pathway. Coenzyme Q, an essential component of the electron transport chain, shuttles electrons between complexes I or II to complex III of the mitochondrial transport chain. This protein appears to play a structural role in stabilizing a complex that contains most of the coenzyme Q biosynthesis enzymes. Mutations in this gene are associated with mitochondrial disorders linked to coenzyme Q deficiency. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51117 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 350 total — 21 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 84
• Cancer dependency (DepMap): dependent in 67.1% of screened cell lines
• MANE Select transcript: NM_016035

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19693
Approved symbol	COQ4
Name	coenzyme Q4
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	CGI-92
Ensembl gene	ENSG00000167113
Ensembl biotype	protein_coding
OMIM	612898
Entrez	51117

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000300452, ENST00000372875, ENST00000461102, ENST00000608951, ENST00000609948, ENST00000861345, ENST00000861346, ENST00000861347, ENST00000926105, ENST00000926106, ENST00000926107, ENST00000926108, ENST00000926109, ENST00000926110, ENST00000970497

RefSeq mRNA: 2 — MANE Select: NM_016035 NM_001305942, NM_016035

CCDS: CCDS6898

Canonical transcript exons

ENST00000300452 — 7 exons

Exon	Start	End
ENSE00001109887	128325143	128325239
ENSE00001109889	128325779	128325881
ENSE00001109891	128332850	128332943
ENSE00001109895	128332153	128332282
ENSE00001109896	128323016	128323147
ENSE00001331352	128322839	128322928
ENSE00001841164	128333474	128334072

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 98.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 70.0447 / max 492.9108, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98748	57.2922	1819
98747	7.6366	1702
98745	2.6631	1292
98746	1.7619	888
98749	0.6909	362

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.23	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.82	gold quality
adenohypophysis	UBERON:0002196	96.55	gold quality
right lobe of thyroid gland	UBERON:0001119	96.46	gold quality
left lobe of thyroid gland	UBERON:0001120	96.37	gold quality
body of pancreas	UBERON:0001150	96.30	gold quality
metanephros cortex	UBERON:0010533	96.07	gold quality
mucosa of transverse colon	UBERON:0004991	96.02	gold quality
right adrenal gland cortex	UBERON:0035827	95.82	gold quality
skin of leg	UBERON:0001511	95.81	gold quality
right adrenal gland	UBERON:0001233	95.77	gold quality
skin of abdomen	UBERON:0001416	95.75	gold quality
left adrenal gland	UBERON:0001234	95.50	gold quality
left adrenal gland cortex	UBERON:0035825	95.44	gold quality
thyroid gland	UBERON:0002046	95.38	gold quality
pituitary gland	UBERON:0000007	95.30	gold quality
esophagus mucosa	UBERON:0002469	95.14	gold quality
lower esophagus mucosa	UBERON:0035834	95.13	gold quality
right lobe of liver	UBERON:0001114	94.88	gold quality
minor salivary gland	UBERON:0001830	94.85	gold quality
apex of heart	UBERON:0002098	94.60	gold quality
transverse colon	UBERON:0001157	94.31	gold quality
body of stomach	UBERON:0001161	94.29	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.87	gold quality
adrenal cortex	UBERON:0001235	93.85	gold quality
endocervix	UBERON:0000458	93.71	gold quality
adrenal gland	UBERON:0002369	93.49	gold quality
right frontal lobe	UBERON:0002810	93.49	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.43	gold quality
zone of skin	UBERON:0000014	93.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting COQ4, 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-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-3928-3P	97.61	66.53	1096
HSA-MIR-597-3P	96.46	68.03	1035

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 67.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• homologous to Coq4p in S.cerevisiae (PMID:11469793)
• Human ortholog of Saccharomyces cerevisiae COQ4 was cloned and characterized. (PMID:18474229)
• Haploinsufficiency in COQ4 resulted in reduced COQ4 expression, CoQ10 content and biosynthetic rate, and activities of respiratory chain complex II+III. (PMID:22368301)
• COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency. (PMID:25658047)
• five recessive missense mutations in COQ4 segregating with lethal neonatal mitochondrial encephalomyopathy in four families of Ashkenzi Jews (PMID:26185144)
• Three genes in our epilepsy cohort (COQ4, DNM1, and PURA), accounting for 14% (3/21) of all novel genetic etiologies identified in patients with epilepsy, were subsequently confirmed in independent publications. (PMID:26795593)
• The COQ4 mutation was CRISPR/Cas9 edited resulting in isogenic, diploid and off-target free COQ4-corrected iPSCs. (PMID:28465093)
• Based on the genetic testing, preimplantation and prenatal diagnoses were performed, confirming that the next offspring of this family was unaffected. Our cases expand the phenotypic spectrum of COQ4 mutations and the genotypic spectrum of Leigh syndrome (PMID:30659264)
• Clinical spectrum in multiple families with primary COQ10 deficiency. (PMID:33215859)
• New pathogenic variants in COQ4 cause ataxia and neurodevelopmental disorder without detectable CoQ10 deficiency in muscle or skin fibroblasts. (PMID:33704555)
• Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease. (PMID:36047608)
• Epilepsy and Coenzyme Q10 deficiency with COQ4 variants. (PMID:37948995)
• Biallelic variants in the COQ4 gene caused hereditary spastic paraplegia predominant phenotype. (PMID:38013626)
• Biallelic COQ4 Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization. (PMID:38014483)
• COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells. (PMID:38295803)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	coq4	ENSDARG00000104733
mus_musculus	Coq4	ENSMUSG00000026798
rattus_norvegicus	Coq4	ENSRNOG00000026691
drosophila_melanogaster	Coq4	FBGN0052174
caenorhabditis_elegans	coq-4	WBGENE00000764

Protein

Protein identifiers

Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial — Q9Y3A0 (reviewed: Q9Y3A0)

Alternative names: 4-hydroxy-3-methoxy-5-polyprenylbenzoate decarboxylase, Coenzyme Q biosynthesis protein 4 homolog

All UniProt accessions (4): Q9Y3A0, Q5T4B9, V9GY32, V9GZ09

UniProt curated annotations — full annotation on UniProt →

Function. Lyase that catalyzes the C1-decarboxylation of 4-hydroxy-3-methoxy-5-(all-trans-decaprenyl)benzoic acid into 2-methoxy-6-(all-trans-decaprenyl)phenol during ubiquinone biosynthesis.

Subunit / interactions. Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Expressed ubiquitously, but at high levels in liver, lung and pancreas.

Disease relevance. Coenzyme Q10 deficiency, primary, 7 (COQ10D7) [MIM:616276] An autosomal recessive disorder resulting from mitochondrial dysfunction and characterized by decreased levels of coenzyme Q10, and severe cardiac or neurologic symptoms soon after birth, usually resulting in death. Rarely, symptoms may have later onset. The disease is caused by variants affecting the gene represented in this entry. Spastic ataxia 10, autosomal recessive (SPAX10) [MIM:620666] A form of spastic ataxia, a heterogeneous group of progressive neurodegenerative disorders characterized by lower-limb spasticity and generalized ataxia with dysarthria, impaired ocular movements, and gait disturbance. SPAX10 is a slowly progressive form with age at onset ranging from infancy to adulthood. Some patients show cerebellar atrophy on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Cofactor biosynthesis; ubiquinone biosynthesis.

Similarity. Belongs to the COQ4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y3A0-1	1	yes
Q9Y3A0-2	2

RefSeq proteins (2): NP_001292871, NP_057119* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007715	Coq4	Family
IPR027540	Coq4_euk	Family

Pfam: PF05019

Catalyzed reactions (Rhea), 1 shown:

• 4-hydroxy-3-methoxy-5-(all-trans-decaprenyl)benzoate + H(+) = 2-methoxy-6-(all-trans-decaprenyl)phenol + CO2 (RHEA:81275)

UniProt features (34 total): sequence variant 23, binding site 4, mutagenesis site 2, transit peptide 1, chain 1, sequence conflict 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3A0-F1	88.56	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 163; 164; 167; 179

Post-translational modifications (1): 108

Mutagenesis-validated functional residues (2):

Position	Phenotype
163–167	abolished zinc-binding.
164	abolished zinc-binding; when associated with a-179. abolished zinc-binding and ability to promote formation of ubiquinon

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2142789	Ubiquinol biosynthesis

MSigDB gene sets: 305 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_KETONE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_KETONE_BIOSYNTHETIC_PROCESS, USF_02, BREDEMEYER_RAG_SIGNALING_NOT_VIA_ATM_UP, MODULE_455, XU_GH1_AUTOCRINE_TARGETS_DN, GOBP_QUINONE_METABOLIC_PROCESS, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_EXTRINSIC_COMPONENT_OF_ORGANELLE_MEMBRANE, GOCC_EXTRINSIC_COMPONENT_OF_MEMBRANE, GOMF_CARBOXY_LYASE_ACTIVITY

GO Biological Process (1): ubiquinone biosynthetic process (GO:0006744)

GO Molecular Function (4): zinc ion binding (GO:0008270), 4-hydroxy-3-methoxy-5-polyprenylbenzoate decarboxylase activity (GO:0120539), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), extrinsic component of mitochondrial inner membrane (GO:0031314), protein-containing complex (GO:0032991), ubiquinone biosynthesis complex (GO:0110142), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ubiquinone metabolic process	1
quinone biosynthetic process	1
transition metal ion binding	1
ubiquinone biosynthetic process	1
carboxy-lyase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial inner membrane	1
extrinsic component of organelle membrane	1
cellular_component	1
catalytic complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COQ4	COQ7	Q99807	962
COQ4	COQ5	Q5HYK3	959
COQ4	COQ6	Q9Y2Z9	954
COQ4	COQ3	Q9NZJ6	953
COQ4	COQ9	O75208	949
COQ4	COQ8A	Q8NI60	919
COQ4	COQ8B	Q96D53	919
COQ4	PDSS1	Q5T2R2	916
COQ4	COQ2	Q96H96	913
COQ4	PDSS2	Q86YH6	874
COQ4	COQ10A	Q96MF6	756
COQ4	COQ10B	Q9H8M1	715
COQ4	ETFDH	Q16134	650
COQ4	ADCK2	Q7Z695	615
COQ4	ADCK1	Q86TW2	577
COQ4	NDUFA9	Q16795	577

IntAct

18 interactions, top by confidence:

A	B	Type	Score
COQ4	COQ7	psi-mi:“MI:0407”(direct interaction)	0.590
COQ7	COQ4	psi-mi:“MI:0407”(direct interaction)	0.590
COQ9	COQ5	psi-mi:“MI:0915”(physical association)	0.590
COQ7	COQ9	psi-mi:“MI:0915”(physical association)	0.590
MAGEA2	COQ4	psi-mi:“MI:0915”(physical association)	0.560
COQ3	COQ4	psi-mi:“MI:0407”(direct interaction)	0.520
COQ4	COQ5	psi-mi:“MI:0407”(direct interaction)	0.520
COQ4	COQ3	psi-mi:“MI:0407”(direct interaction)	0.520
COQ4	COQ6	psi-mi:“MI:0407”(direct interaction)	0.520
COQ5	COQ4	psi-mi:“MI:0407”(direct interaction)	0.520
COQ6	COQ4	psi-mi:“MI:0407”(direct interaction)	0.520
COQ4	COQ5	psi-mi:“MI:0914”(association)	0.520
COQ4	COQ9	psi-mi:“MI:0914”(association)	0.500
COQ4	TRMU	psi-mi:“MI:0914”(association)	0.350
COQ4	MAGEA2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (43): COQ5 (Affinity Capture-Western), COQ4 (Affinity Capture-Western), COQ4 (Reconstituted Complex), COQ7 (Reconstituted Complex), COQ4 (Reconstituted Complex), COQ4 (Affinity Capture-MS), COQ5 (Affinity Capture-MS), COQ9 (Affinity Capture-MS), COQ3 (Affinity Capture-MS), COQ6 (Affinity Capture-MS), MRPL1 (Affinity Capture-MS), MRPS16 (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), ECH1 (Affinity Capture-MS), MRPL23 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A1A4Q9, A5YM72, A6NLP5, D3KCC4, I3L5V6, O43292, P10938, Q00973, Q05B52, Q09200, Q10468, Q14623, Q148G5, Q16586, Q2V8X7, Q3SZV0, Q561R2, Q5E9M9, Q5M868, Q5ZL13, Q66H45, Q69ZF3, Q6P3D0, Q6P7A1, Q6P9Z4, Q6SZW1, Q6TEC1, Q6ZPS2, Q7TMC8, Q864R5, Q86TX2, Q8IXI1, Q8N0W3, Q8N3Y3, Q8N6R0, Q8NF37, Q8NI29, Q8TCD5, Q8VBW8

Diamond homologs: A0DUC3, A0E513, A1CJA9, A1D871, A3LXH5, A4H5X0, A4HU65, A4RBZ3, A5ABP2, A5DMG2, A6QW12, A6ZYG1, A7SNR3, A7TMI3, A8P488, A9JR86, A9JS49, B0D5R2, B0WH96, B0XLA4, B0XYZ8, B2AU15, B2WBF0, B3LG81, B3M6C8, B3NHV5, B4H6M2, B4HKS2, B4N6G2, B4PJV6, B4QNU8, B5VG95, B6HEJ5, B6QTE1, B8MLN6, B8NV05, B9W797, C0HL93, C0HL94, C0NJU0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COQ4	“form complex”	“CoQ biosynthetic complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	15
Uncertain significance	120
Likely benign	148
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1368452	NM_016035.5(COQ4):c.385dup (p.Arg129fs)	Pathogenic
1455564	NM_016035.5(COQ4):c.19_20del (p.Pro7fs)	Pathogenic
1685665	NM_016035.5(COQ4):c.202G>A (p.Asp68Asn)	Pathogenic
1686776	NM_016035.5(COQ4):c.130_137dup (p.Leu47fs)	Pathogenic
189199	NM_016035.5(COQ4):c.433C>G (p.Arg145Gly)	Pathogenic
189200	NM_016035.5(COQ4):c.421C>T (p.Arg141Ter)	Pathogenic
189202	NM_016035.5(COQ4):c.155T>C (p.Leu52Ser)	Pathogenic
189203	NM_016035.5(COQ4):c.518CCA[1] (p.Thr174del)	Pathogenic
2099803	NM_016035.5(COQ4):c.223G>T (p.Glu75Ter)	Pathogenic
2102003	NM_016035.5(COQ4):c.662G>A (p.Trp221Ter)	Pathogenic
2686020	NM_016035.5(COQ4):c.434G>A (p.Arg145His)	Pathogenic
2686021	NM_016035.5(COQ4):c.719G>A (p.Arg240His)	Pathogenic
2686023	NM_016035.5(COQ4):c.87dup (p.Arg30Ter)	Pathogenic
280320	NM_016035.5(COQ4):c.23_33del (p.Val8fs)	Pathogenic
2894348	NM_016035.5(COQ4):c.142C>T (p.Gln48Ter)	Pathogenic
3017586	NM_016035.5(COQ4):c.130_137del (p.Thr44fs)	Pathogenic
3700679	NM_016035.5(COQ4):c.626+1G>C	Pathogenic
476179	NM_016035.5(COQ4):c.370G>A (p.Gly124Ser)	Pathogenic
476186	NM_016035.5(COQ4):c.67dup (p.Ala23fs)	Pathogenic
638639	NM_016035.5(COQ4):c.371G>T (p.Gly124Val)	Pathogenic
915899	NM_016035.5(COQ4):c.305G>A (p.Arg102His)	Pathogenic
1029574	NM_016035.5(COQ4):c.2T>C (p.Met1Thr)	Likely pathogenic
1679218	NM_016035.5(COQ4):c.540del (p.Ile180fs)	Likely pathogenic
2101637	NM_016035.5(COQ4):c.70+1G>A	Likely pathogenic
2429966	NM_016035.5(COQ4):c.230C>T (p.Thr77Ile)	Likely pathogenic
2897600	NM_016035.5(COQ4):c.299+1G>A	Likely pathogenic
3076320	NM_016035.5(COQ4):c.55C>T (p.Gln19Ter)	Likely pathogenic
3342649	NM_016035.5(COQ4):c.211G>A (p.Ala71Thr)	Likely pathogenic
3596460	NM_016035.5(COQ4):c.627-1G>A	Likely pathogenic
3651110	NM_016035.5(COQ4):c.70+2C>A	Likely pathogenic

SpliceAI

877 predictions. Top by Δscore:

Variant	Effect	Δscore
9:128323015:GAAAT:G	acceptor_gain	1.0000
9:128323144:CACGG:C	donor_loss	1.0000
9:128323145:ACGGT:A	donor_loss	1.0000
9:128323146:CGGTA:C	donor_loss	1.0000
9:128323148:G:GG	donor_gain	1.0000
9:128323148:GTAAG:G	donor_loss	1.0000
9:128323149:T:G	donor_loss	1.0000
9:128325240:G:GG	donor_gain	1.0000
9:128325882:G:GG	donor_gain	1.0000
9:128332939:GCTCA:G	donor_gain	1.0000
9:128332940:CTCAG:C	donor_loss	1.0000
9:128332941:TCA:T	donor_gain	1.0000
9:128332941:TCAGT:T	donor_loss	1.0000
9:128332942:CA:C	donor_gain	1.0000
9:128332942:CAGTA:C	donor_loss	1.0000
9:128332943:AGTAA:A	donor_loss	1.0000
9:128332944:G:GG	donor_gain	1.0000
9:128332944:GTAA:G	donor_loss	1.0000
9:128332945:TAAGT:T	donor_loss	1.0000
9:128323014:A:AG	acceptor_gain	0.9900
9:128323014:A:T	acceptor_loss	0.9900
9:128323015:G:GA	acceptor_loss	0.9900
9:128323015:G:GG	acceptor_gain	0.9900
9:128323015:GA:G	acceptor_gain	0.9900
9:128323015:GAA:G	acceptor_gain	0.9900
9:128323015:GAAA:G	acceptor_gain	0.9900
9:128325210:G:GT	donor_gain	0.9900
9:128325237:GCA:G	donor_gain	0.9900
9:128325851:TCGC:T	donor_gain	0.9900
9:128325878:GAAC:G	donor_gain	0.9900

AlphaMissense

1681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:128325867:T:C	F130L	0.995
9:128325869:C:A	F130L	0.995
9:128325869:C:G	F130L	0.995
9:128332249:C:G	H167D	0.992
9:128332866:A:C	K183N	0.990
9:128332866:A:T	K183N	0.990
9:128332229:G:C	R160P	0.989
9:128332875:G:C	E186D	0.989
9:128332875:G:T	E186D	0.989
9:128332237:C:G	H163D	0.988
9:128332241:A:C	D164A	0.988
9:128332853:A:T	E179V	0.987
9:128332865:A:T	K183I	0.987
9:128332241:A:T	D164V	0.986
9:128332867:T:A	W184R	0.986
9:128332867:T:C	W184R	0.986
9:128325868:T:C	F130S	0.985
9:128332249:C:A	H167N	0.984
9:128325206:T:C	M89T	0.983
9:128332186:T:C	F146L	0.983
9:128332188:C:A	F146L	0.983
9:128332188:C:G	F146L	0.983
9:128332242:C:A	D164E	0.983
9:128332242:C:G	D164E	0.983
9:128332251:C:A	H167Q	0.983
9:128332251:C:G	H167Q	0.983
9:128332876:G:C	A187P	0.982
9:128332870:T:C	F185L	0.981
9:128332872:T:A	F185L	0.981
9:128332872:T:G	F185L	0.981

dbSNP variants (sampled 300 via entrez): RS1000035417 (9:128334419 G>A,C), RS1000153078 (9:128328550 G>A), RS1000240845 (9:128323042 G>A), RS1000315946 (9:128323258 A>G), RS1000578493 (9:128324245 T>C), RS1000600163 (9:128328858 G>A), RS1000748186 (9:128324068 C>T), RS1001085803 (9:128334484 G>A), RS1001350510 (9:128322807 C>T), RS1001639330 (9:128328488 C>T), RS1002093248 (9:128323800 A>G,T), RS1002126230 (9:128323938 C>T), RS1002142728 (9:128333550 CTGTACTA>C), RS1002242473 (9:128327714 G>A), RS1002294788 (9:128327895 T>TAAC)

Disease associations

OMIM: gene MIM:612898 | disease phenotypes: MIM:616276, MIM:620666, MIM:108600, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (4): neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (MONDO:0014562), spastic ataxia 10, autosomal recessive (MONDO:0958009), spastic ataxia (MONDO:0017845), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (3): Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (Orphanet:457185), Spastic ataxia (Orphanet:316226), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

84 total (30 of 84 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000365	Hearing impairment
HP:0000505	Visual impairment
HP:0000639	Nystagmus
HP:0001063	Acrocyanosis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001271	Polyneuropathy
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001310	Dysmetria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001629	Ventricular septal defect
HP:0001639	Hypertrophic cardiomyopathy
HP:0001643	Patent ductus arteriosus
HP:0001662	Bradycardia
HP:0001987	Hyperammonemia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_186	Obesity-related traits	7.000000e-06
GCST001762_726	Obesity-related traits	6.000000e-06
GCST005951_65	Body mass index	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

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
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Leflunomide	decreases expression	2
Air Pollutants	increases expression, affects expression, increases abundance	2
Hydrogen Peroxide	affects cotreatment, decreases expression, increases expression	2
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
MT19c compound	decreases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone	increases expression	1
Doxorubicin	decreases expression	1
Hydralazine	increases expression, affects cotreatment	1
Manganese	decreases expression, increases abundance	1
Ozone	affects expression, increases abundance	1
Phenobarbital	affects expression	1
Smoke	increases abundance, increases expression	1
Theophylline	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8HP	CQ4ed-iPSC	Induced pluripotent stem cell	Female
CVCL_E1UB	HAP1 COQ4 (-)	Cancer cell line	Male
CVCL_QY04	CQ4-iPSC clone 14	Induced pluripotent stem cell	Female
CVCL_UM97	CQ4-iPSC clone 34	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

53 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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
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