CHCHD10

Summary

CHCHD10 (coiled-coil-helix-coiled-coil-helix domain containing 10, HGNC:15559) is a protein-coding gene on chromosome 22q11.23, encoding Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (Q8WYQ3). May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure.

This gene encodes a mitochondrial protein that is enriched at cristae junctions in the intermembrane space. It may play a role in cristae morphology maintenance or oxidative phosphorylation. Mutations in this gene cause frontotemporal dementia and/or amyotrophic lateral sclerosis-2. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 7 and 19.

Source: NCBI Gene 400916 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 284 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 129
• MANE Select transcript: NM_213720

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15559
Approved symbol	CHCHD10
Name	coiled-coil-helix-coiled-coil-helix domain containing 10
Location	22q11.23
Locus type	gene with protein product
Status	Approved
Aliases	N27C7-4, MIX17A
Ensembl gene	ENSG00000250479
Ensembl biotype	protein_coding
OMIM	615903
Entrez	400916

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000401675, ENST00000484558, ENST00000517886, ENST00000520222, ENST00000523865, ENST00000878116, ENST00000878117, ENST00000878118, ENST00000878119, ENST00000878120, ENST00000878121

RefSeq mRNA: 2 — MANE Select: NM_213720 NM_001301339, NM_213720

CCDS: CCDS13815, CCDS77659

Canonical transcript exons

ENST00000484558 — 4 exons

Exon	Start	End
ENSE00002064421	23767374	23767593
ENSE00002091168	23767834	23767972
ENSE00003567448	23766128	23766275
ENSE00003899836	23765834	23766026

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 144.2416 / max 1739.0887, expressed in 1811 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193334	142.7951	1811
193331	0.5276	231
193333	0.4438	230
209419	0.2396	97
193332	0.2354	100

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.82	gold quality
heart left ventricle	UBERON:0002084	99.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.66	gold quality
right atrium auricular region	UBERON:0006631	99.54	gold quality
skeletal muscle tissue	UBERON:0001134	99.51	gold quality
gastrocnemius	UBERON:0001388	99.51	gold quality
mucosa of transverse colon	UBERON:0004991	99.46	gold quality
primary visual cortex	UBERON:0002436	99.34	gold quality
right lobe of liver	UBERON:0001114	99.29	gold quality
adult mammalian kidney	UBERON:0000082	99.14	gold quality
superior frontal gyrus	UBERON:0002661	99.11	gold quality
heart	UBERON:0000948	99.08	gold quality
putamen	UBERON:0001874	99.07	gold quality
right lobe of thyroid gland	UBERON:0001119	99.03	gold quality
muscle of leg	UBERON:0001383	99.01	gold quality
nucleus accumbens	UBERON:0001882	99.01	gold quality
caudate nucleus	UBERON:0001873	99.00	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.00	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.99	gold quality
left lobe of thyroid gland	UBERON:0001120	98.93	gold quality
cortex of kidney	UBERON:0001225	98.93	gold quality
liver	UBERON:0002107	98.91	gold quality
metanephros cortex	UBERON:0010533	98.89	gold quality
prefrontal cortex	UBERON:0000451	98.88	gold quality
transverse colon	UBERON:0001157	98.87	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.87	gold quality
thyroid gland	UBERON:0002046	98.83	gold quality
frontal cortex	UBERON:0001870	98.78	gold quality
anterior cingulate cortex	UBERON:0009835	98.77	gold quality
right frontal lobe	UBERON:0002810	98.75	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	115.02
E-HCAD-9	yes	58.21
E-MTAB-8410	yes	54.73
E-HCAD-4	yes	51.58
E-MTAB-7316	yes	25.88
E-GEOD-135922	yes	13.94
E-ANND-3	yes	12.81
E-MTAB-8271	yes	9.95
E-CURD-135	no	337.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting CHCHD10, 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-6748-5P	100.00	65.81	1057
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-599	98.32	66.99	1037
HSA-MIR-134-3P	96.83	66.22	1001
HSA-MIR-1298-3P	94.05	64.84	620

Literature-anchored findings (GeneRIF, showing 40)

• CHCHD10 and GBAS are involved in oxidative phosphorylation; CHCHD10 plays role in complex IV activity. (PMID:20888800)
• Functional annotation of CHCHD10 as mitochondrial protein with function related to cytochrome-c-oxidase (complex IV) activity. (PMID:20888800)
• Mitochondrial disease (CHCHD10 mutation) may be at the origins of some frontotemporal dementia and amyotrophic lateral sclerosis phenotypes. (PMID:24934289)
• CHCHD10 encodes a protein located in the mitochondrial intermembrane space and is likely involved in mitochondrial genome stability and maintenance of cristae junctions. (PMID:25155093)
• findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria. (PMID:25193783)
• The results of this study support this estimation, and suggest that the real prevalence of CHCHD10-related disease in Finland is probably much higher. (PMID:25428574)
• CHCHD10 mutations account for approximately 1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs. (PMID:25726362)
• Even within the same family, the p.Gly66Val variant can cause variable phenotypes ranging from CMT2-type axonal neuropathy to spinal muscular atrophy, which may also present as an ALS-like disease. (PMID:26224640)
• CHCHD10 P34S variant is not associated with ALS in a UK cohort of familial and sporadic patients. (PMID:26344877)
• CHCHD10 was found to not be a highly penetrant pathogenic variant for amyotrophic lateral sclerosis and frontotemporal dementia. (PMID:26362910)
• Disassembly of the mitochondrial contact site and cristae organizing system complex secondary to CHCHD10 mutations leads to mitochondrial dysfunction including inhibition of apoptosis. (PMID:26666268)
• CHCHD10 gene mutation appears to be an uncommon cause of amyotrophic lateral sclerosis in Chinese populations. (PMID:27056076)
• No mutations were identified in CHCHD10 in ALS cases of Chinese ancestry. (PMID:27077676)
• CHCHD10 is not a primary cause of familial amyotrophic lateral sclerosis in France. (PMID:27095681)
• that CHCHD10 mutation was presented in different types of dementia (PMID:27578015)
• In Finnish cohorts with motor neuron disease, heterozygous mutation c.197G>T p.G66V in CHCHD10 was detected in 23 patients. In two siblings with a cramping disorder and mitochondrial pathology, heterozygous c.100C>T p.P34S was detected. (PMID:27810918)
• Its mutations were seen in patients with ALS and frontotemporal dementia. (PMID:28069311)
• Its mutation is not arelevant cause of Parkinson’s disease in Italian population. (PMID:28108040)
• Its mutations are found in Chinese patients with amyotrophic lateral sclerosis. (PMID:28318595)
• Screening of MAPT, GRN and CHCHD10 genes in Chinese patients with frontotemporal dementia (FTD) identified about 4.9% mutation carriers. Among the known FTD causative genes tested, MAPT and CHCHD10 play the most important roles in Chinese patients with sporadic FTD. (PMID:28462717)
• CHCHD10 mutations have a role in cytoplasmic TDP-43 accumulation and synaptic integrity (PMID:28585542)
• Evidence obtained from in vitro and in vivo studies suggest that CHCHD10 mutants cause disease through a gain of toxic function mechanism, rather than a loss of function. (PMID:29112723)
• Results indicate that CHCHD10-CHCHD2 complexes are necessary for efficient mitochondrial respiration, and support a role for mitochondrial dysfunction in some patients with ALS. (PMID:29121267)
• This studt did not found statistical differences in genotypic distribution between Parkinson’s disease cases and control individuals for these variants in CHCHD10. (PMID:29249678)
• Data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10. (PMID:29315381)
• Homozygous Pro96Thr mutation in CHCHD10 might be pathogenic to mitochondrial myopathy. (PMID:29519717)
• results reveal that CHCHD10 positively regulates mitochondrial respiration and contributes to transcriptional repression of ORE-containing genes in the nucleus, and that genetic CHCHD10 variants are impaired in these activities. (PMID:29540477)
• A novel CHCHD10 mutation is linked with mitochondrial import deficit in ALS. (PMID:29789341)
• This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants (PMID:30014597)
• these findings demonstrate that differences in the stability and mutual affinity of CHCHD2 and CHCHD10 regulate their heterodimerization in response to mitochondrial distress, revealing an unanticipated link between Parkinson Disease and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia pathogenesis. (PMID:30084972)
• genetic variation is not a common cause of amyotrophic lateral sclerosis and frontotemporal dementia in Australia, but neuron-specific role and a loss of function may be (PMID:31690696)
• CHCHD10-regulated OPA1-mitofilin complex mediates TDP-43-induced mitochondrial phenotypes associated with frontotemporal dementia. (PMID:32369233)
• ALS and Parkinson’s disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons. (PMID:32437855)
• Meta-analysis of the association between CHCHD10 Pro34Ser variant and the risk of amyotrophic lateral sclerosis. (PMID:32651855)
• Multi-OMICS study of a CHCHD10 variant causing ALS demonstrates metabolic rewiring and activation of endoplasmic reticulum and mitochondrial unfolded protein responses. (PMID:33749723)
• Structures of the Wild-Type and S59L Mutant CHCHD10 Proteins Important in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia. (PMID:35349255)
• CHCHD10 and SLP2 control the stability of the PHB complex: a key factor for motor neuron viability. (PMID:35656794)
• CHCHD10 Modulates Thermogenesis of Adipocytes by Regulating Lipolysis. (PMID:35709007)
• Modulation of synaptic plasticity, motor unit physiology, and TDP-43 pathology by CHCHD10. (PMID:35787294)
• Effects of the Jokela type of spinal muscular atrophy-related G66V mutation on the structural ensemble characteristics of CHCHD10. (PMID:36625206)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	chchd10	ENSDARG00000010717
mus_musculus	Chchd10	ENSMUSG00000049422
rattus_norvegicus	Chchd10	ENSRNOG00000028356
drosophila_melanogaster	CG31007	FBGN0051007
caenorhabditis_elegans		WBGENE00007630

Paralogs (1): CHCHD2 (ENSG00000106153)

Protein

Protein identifiers

Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial — Q8WYQ3 (reviewed: Q8WYQ3)

Alternative names: Protein N27C7-4

All UniProt accessions (4): B5MBW9, E5RGN4, E5RH03, Q8WYQ3

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure.

Subcellular location. Mitochondrion intermembrane space.

Tissue specificity. Ubiquitously expressed. Higher expression is observed in heart and liver.

Disease relevance. Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (FTDALS2) [MIM:615911] A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. The disease is caused by variants affecting the gene represented in this entry. The pathological events leading to disease involve fragmentation of the mitochondrial network, mitochondrial ultrastructural abnormalities including loss, disorganization and dilatation of cristae, and mitochondrial dysfunction associated with respiratory chain deficiency. Spinal muscular atrophy, Jokela type (SMAJ) [MIM:615048] An autosomal dominant, slowly progressive, lower motor neuron disease. SMAJ is characterized by adult-onset of muscle cramps and fasciculations affecting the proximal and distal muscles of the upper and lower limbs. The disorder results in weakness and mild muscle atrophy later in life. The disease is caused by variants affecting the gene represented in this entry. Myopathy, isolated mitochondrial, autosomal dominant (IMMD) [MIM:616209] A mitochondrial myopathy presenting with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. The disorder is slowly progressive, with later involvement of facial muscles, muscles of the upper limbs, and distal muscles. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001288268, NP_998885* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010625	CHCH	Domain
IPR055304	CHCHD2/10-like	Family

Pfam: PF06747

UniProt features (17 total): sequence variant 5, compositionally biased region 3, disulfide bond 2, region of interest 2, short sequence motif 2, transit peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9CWW	ELECTRON MICROSCOPY	2.3
9OYW	ELECTRON MICROSCOPY	2.63
9OYQ	ELECTRON MICROSCOPY	2.7
9OYS	ELECTRON MICROSCOPY	3.06
9OYO	ELECTRON MICROSCOPY	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYQ3-F1	63.01	0.07

Functional residue map

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

Disulfide bonds (2): 102–132, 112–122

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import

MSigDB gene sets: 431 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, TGACCTY_ERR1_Q2, MARTINEZ_RB1_TARGETS_UP, TRAYNOR_RETT_SYNDROM_DN, GOBP_INNER_MITOCHONDRIAL_MEMBRANE_ORGANIZATION, YY1_02, LANDIS_ERBB2_BREAST_PRENEOPLASTIC_DN, GOCC_MITOCHONDRIAL_ENVELOPE, LANDIS_ERBB2_BREAST_TUMORS_65_DN, GOBP_MEMBRANE_ORGANIZATION, RICKMAN_TUMOR_DIFFERENTIATED_MODERATELY_VS_POORLY_UP, MARTINEZ_RB1_AND_TP53_TARGETS_UP

GO Biological Process (3): mitochondrion organization (GO:0007005), mitochondrial membrane organization (GO:0007006), inner mitochondrial membrane organization (GO:0007007)

GO Molecular Function (2): molecular_function (GO:0003674), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), MICOS complex (GO:0061617)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
organelle organization	1
mitochondrion	1
mitochondrion organization	1
membrane organization	1
mitochondrial membrane organization	1
binding	1
cytoplasm	1
mitochondrial envelope	1
organelle envelope lumen	1
inner mitochondrial membrane protein complex	1

Protein interactions and networks

STRING

1210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHCHD10	CHCHD6	Q9BRQ6	757
CHCHD10	CHCHD3	Q9NX63	751
CHCHD10	MICOS13	Q5XKP0	738
CHCHD10	MATR3	P43243	736
CHCHD10	NEK1	Q96PY6	733
CHCHD10	ATXN2	Q99700	730
CHCHD10	ALS2	Q96Q42	724
CHCHD10	C9orf72	Q96LT7	721
CHCHD10	TARDBP	Q13148	712
CHCHD10	UBQLN2	Q9UHD9	702
CHCHD10	VCP	P55072	700
CHCHD10	FUS	P35637	664
CHCHD10	APOO	Q9BUR5	663
CHCHD10	APOOL	Q6UXV4	654
CHCHD10	OPTN	Q96CV9	647

IntAct

27 interactions, top by confidence:

A	B	Type	Score
CHCHD10	CHCHD2	psi-mi:“MI:0915”(physical association)	0.710
CHCHD10	CHCHD2	psi-mi:“MI:0403”(colocalization)	0.710
CHCHD2	CHCHD10	psi-mi:“MI:0915”(physical association)	0.710
CHCHD10	CLPX	psi-mi:“MI:0914”(association)	0.640
CHCHD10	IMMT	psi-mi:“MI:0915”(physical association)	0.600
IMMT	CHCHD10	psi-mi:“MI:0914”(association)	0.600
IMMT	CHCHD10	psi-mi:“MI:0915”(physical association)	0.600
IMMT	CHCHD10	psi-mi:“MI:2364”(proximity)	0.600
CHCHD6	CHCHD10	psi-mi:“MI:2364”(proximity)	0.470
ABL1	CHCHD10	psi-mi:“MI:0407”(direct interaction)	0.440
CHCHD10	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CFTR	CHCHD10	psi-mi:“MI:0915”(physical association)	0.370
CHCHD10	ZNF593	psi-mi:“MI:0914”(association)	0.350
CHCHD10	TIMM44	psi-mi:“MI:0914”(association)	0.350
CHCHD2	POLRMT	psi-mi:“MI:0914”(association)	0.350
CHCHD10	RNASEH1	psi-mi:“MI:0914”(association)	0.350
CHCHD10	ACSL4	psi-mi:“MI:0914”(association)	0.350
CHCHD2	ACSL4	psi-mi:“MI:0914”(association)	0.350
CHCHD10	AKR7A2	psi-mi:“MI:0914”(association)	0.350
CHCHD2	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
SLC15A3	GXYLT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (107): RNASEH1 (Affinity Capture-MS), CHCHD10 (Affinity Capture-MS), CHCHD10 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), STARD7 (Affinity Capture-MS), CLPX (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), SLC25A6 (Affinity Capture-MS), TIMM44 (Affinity Capture-MS), OXA1L (Affinity Capture-MS), GHITM (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), USMG5 (Affinity Capture-MS), IMMT (Affinity Capture-MS)

ESM2 similar proteins: A0A0H2URK1, A0A8J9SEV3, A1X158, A7MMK9, A7ZM89, A8A0H2, A8AWU7, A8XV37, B4T594, B5BKB2, B5XWP9, B5Z463, B6IB67, B7NB83, B7URX0, B8NM66, O04132, P02401, P04929, P04930, P05227, P05228, P05387, P11006, P11024, P11734, P12027, P15941, P17437, P42899, P46804, P80684, P80686, P99027, Q02192, Q06811, Q0THJ8, Q13423, Q29315, Q2G0L5

Diamond homologs: Q09254, Q5T1J5, Q8WYQ3, Q9D1L0, Q9Y6H1, Q03667

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	146
Likely benign	96
Benign	14

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1452852	NM_213720.3(CHCHD10):c.44_45delinsTT (p.Arg15Leu)	Pathogenic
180221	NM_213720.3(CHCHD10):c.197G>T (p.Gly66Val)	Pathogenic
242618	NM_213720.3(CHCHD10):c.172G>C (p.Gly58Arg)	Pathogenic
997818	Single allele	Pathogenic
1808567	GRCh37/hg19 22q11.23(chr22:23650872-25002483)x3	Likely pathogenic

SpliceAI

630 predictions. Top by Δscore:

Variant	Effect	Δscore
22:23766122:A:AC	donor_gain	1.0000
22:23766123:C:CC	donor_gain	1.0000
22:23766124:TCA:T	donor_loss	1.0000
22:23766125:CA:C	donor_loss	1.0000
22:23766126:A:AT	donor_loss	1.0000
22:23767591:CGG:C	acceptor_gain	1.0000
22:23766123:CT:C	donor_gain	0.9900
22:23766123:CTCA:C	donor_gain	0.9900
22:23766126:A:AC	donor_gain	0.9900
22:23766127:C:CC	donor_gain	0.9900
22:23767368:GCTCA:G	donor_loss	0.9900
22:23767369:CTCAC:C	donor_loss	0.9900
22:23767370:TCAC:T	donor_loss	0.9900
22:23767371:CACCT:C	donor_loss	0.9900
22:23767373:C:T	donor_loss	0.9900
22:23767373:CCTG:C	donor_gain	0.9900
22:23767589:GGCGG:G	acceptor_gain	0.9900
22:23767590:GCGG:G	acceptor_gain	0.9900
22:23767591:CGGC:C	acceptor_gain	0.9900
22:23767594:C:CC	acceptor_gain	0.9900
22:23767828:TCACA:T	donor_loss	0.9900
22:23767829:CACA:C	donor_loss	0.9900
22:23767831:CA:C	donor_gain	0.9900
22:23767832:AC:A	donor_loss	0.9900
22:23767833:CCTGG:C	donor_gain	0.9900
22:23767863:T:TA	donor_gain	0.9900
22:23767864:C:A	donor_gain	0.9900
22:23766022:CAGAC:C	acceptor_gain	0.9800
22:23766024:GACC:G	acceptor_loss	0.9800
22:23766025:ACCTG:A	acceptor_loss	0.9800

AlphaMissense

899 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:23767468:G:T	A56D	1.000
22:23767480:G:T	A52D	1.000
22:23766211:A:C	F109C	0.999
22:23766211:A:G	F109S	0.999
22:23767444:A:T	V64D	0.999
22:23767450:C:T	G62E	0.999
22:23767456:G:T	A60D	0.999
22:23767462:C:T	G58D	0.999
22:23767477:G:T	A53E	0.999
22:23767489:G:T	A49E	0.999
22:23766172:C:G	C122S	0.998
22:23766173:A:T	C122S	0.998
22:23766202:C:G	C112S	0.998
22:23766203:A:T	C112S	0.998
22:23767457:C:G	A60P	0.998
22:23767463:C:G	G58R	0.998
22:23767465:A:T	V57E	0.998
22:23767474:C:T	G54E	0.998
22:23766151:A:G	L129P	0.997
22:23766172:C:T	C122Y	0.997
22:23766200:A:G	S113P	0.997
22:23766201:A:C	C112W	0.997
22:23766202:C:T	C112Y	0.997
22:23767453:A:T	V61E	0.997
22:23767475:C:G	G54R	0.997
22:23767475:C:T	G54R	0.997
22:23767478:C:G	A53P	0.997
22:23767481:C:G	A52P	0.997
22:23767492:A:T	M48K	0.997
22:23766142:C:G	C132S	0.996

dbSNP variants (sampled 300 via entrez): RS1000021202 (22:23767721 C>A), RS1000462749 (22:23765941 T>C), RS1000576672 (22:23766146 GC>G), RS1001129477 (22:23768200 C>A,T), RS1001389227 (22:23768019 G>A,C), RS1002030198 (22:23765436 T>C,G), RS1002136767 (22:23767157 C>T), RS1002798241 (22:23769929 T>TA), RS1002920523 (22:23769829 C>T), RS1003059358 (22:23769549 C>G), RS1003299824 (22:23769466 C>T), RS1003997041 (22:23765649 T>C), RS1005249865 (22:23769855 A>T), RS1005699174 (22:23767914 G>A,T), RS1005830042 (22:23768580 G>A,C)

Disease associations

OMIM: gene MIM:615903 | disease phenotypes: MIM:615048, MIM:615911, MIM:616209

GenCC curated gene-disease

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 2	Strong	Autosomal dominant
lower motor neuron syndrome with late-adult onset	Strong	Autosomal dominant
autosomal dominant mitochondrial myopathy with exercise intolerance	Strong	Autosomal dominant
frontotemporal dementia with motor neuron disease	Supportive	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AD
frontotemporal dementia and/or amyotrophic lateral sclerosis 2	Moderate	AD

Mondo (7): lower motor neuron syndrome with late-adult onset (MONDO:0014025), frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (MONDO:0014395), autosomal dominant mitochondrial myopathy with exercise intolerance (MONDO:0014532), amyotrophic lateral sclerosis (MONDO:0004976), intellectual disability (MONDO:0001071), epilepsy (MONDO:0005027), frontotemporal dementia with motor neuron disease (MONDO:0017161)

Orphanet (5): Frontotemporal dementia with motor neuron disease (Orphanet:275872), Lower motor neuron syndrome with late-adult onset (Orphanet:276435), Autosomal dominant mitochondrial myopathy with exercise intolerance (Orphanet:457050), Amyotrophic lateral sclerosis (Orphanet:803), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

129 total (30 of 129 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000011	Neurogenic bladder
HP:0000217	Xerostomia
HP:0000407	Sensorineural hearing impairment
HP:0000508	Ptosis
HP:0000605	Supranuclear gaze palsy
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000727	Frontal lobe dementia
HP:0000734	Disinhibition
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001283	Bulbar palsy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001308	Tongue fasciculations
HP:0001324	Muscle weakness
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001761	Pes cavus
HP:0001763	Pes planus
HP:0001765	Hammertoe

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009860_10	IgG N-glycosylation phenotypes (multivariate analysis)	1.000000e-41
GCST90002388_599	Lymphocyte count	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005193	serum IgG glycosylation measurement
EFO:0004587	lymphocyte count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C566288	Frontotemporal Dementia With Motor Neuron Disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	decreases expression, increases expression	3
Cyclosporine	increases expression	3
bisphenol A	affects expression, affects cotreatment, increases methylation	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression	2
FR900359	increases phosphorylation	1
ginger extract	increases abundance, increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic 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
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_E4TY	KOLF2.1J CHCHD10 1.8kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7JV	KOLF2.1J CHCHD10 R15L SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7JW	KOLF2.1J CHCHD10 R15L SNV/WT	Induced pluripotent stem cell	Male
CVCL_SI75	HAP1 CHCHD10 (-) 1	Cancer cell line	Male
CVCL_SI76	HAP1 CHCHD10 (-) 2	Cancer cell line	Male
CVCL_SI77	HAP1 CHCHD10 (-) 3	Cancer cell line	Male
CVCL_SI78	HAP1 CHCHD10 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS