CHCHD2

Summary

CHCHD2 (coiled-coil-helix-coiled-coil-helix domain containing 2, HGNC:21645) is a protein-coding gene on chromosome 7p11.2, encoding Coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (Q9Y6H1). Transcription factor. It is a selective cancer dependency (DepMap: 59.6% of cell lines).

The protein encoded by this gene belongs to a class of eukaryotic CX(9)C proteins characterized by four cysteine residues spaced ten amino acids apart from one another. These residues form disulfide linkages that define a CHCH fold. In response to stress, the protein translocates from the mitochondrial intermembrane space to the nucleus where it binds to a highly conserved 13 nucleotide oxygen responsive element in the promoter of cytochrome oxidase 4I2, a subunit of the terminal enzyme of the electron transport chain. In concert with recombination signal sequence-binding protein J, binding of this protein activates the oxygen responsive element at four percent oxygen. In addition, it has been shown that this protein is a negative regulator of mitochondria-mediated apoptosis. In response to apoptotic stimuli, mitochondrial levels of this protein decrease, allowing BCL2-associated X protein to oligomerize and activate the caspase cascade. Pseudogenes of this gene are found on multiple chromosomes. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51142 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease 22, autosomal dominant (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 112 total — 2 pathogenic
• Phenotypes (HPO): 16
• Cancer dependency (DepMap): dependent in 59.6% of screened cell lines
• MANE Select transcript: NM_016139

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21645
Approved symbol	CHCHD2
Name	coiled-coil-helix-coiled-coil-helix domain containing 2
Location	7p11.2
Locus type	gene with protein product
Status	Approved
Aliases	MIX17B, MNRR1
Ensembl gene	ENSG00000106153
Ensembl biotype	protein_coding
OMIM	616244
Entrez	51142

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000395422, ENST00000473095, ENST00000716930, ENST00000962118, ENST00000962119

RefSeq mRNA: 2 — MANE Select: NM_016139 NM_001320327, NM_016139

CCDS: CCDS5526

Canonical transcript exons

ENST00000395422 — 4 exons

Exon	Start	End
ENSE00000685592	56102867	56103011
ENSE00001370638	56101573	56101861
ENSE00003501256	56104226	56104475
ENSE00004031152	56106364	56106476

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 99.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 190.0738 / max 873.4784, expressed in 1782 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84182	176.3964	1782
84181	12.7717	1637
204452	0.9056	418

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.68	gold quality
right adrenal gland cortex	UBERON:0035827	99.68	gold quality
left adrenal gland	UBERON:0001234	99.63	gold quality
left adrenal gland cortex	UBERON:0035825	99.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.49	gold quality
gastrocnemius	UBERON:0001388	99.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.40	gold quality
adenohypophysis	UBERON:0002196	99.38	gold quality
ganglionic eminence	UBERON:0004023	99.36	gold quality
adrenal tissue	UBERON:0018303	99.36	gold quality
muscle of leg	UBERON:0001383	99.34	gold quality
mucosa of transverse colon	UBERON:0004991	99.33	gold quality
right frontal lobe	UBERON:0002810	99.30	gold quality
anterior cingulate cortex	UBERON:0009835	99.30	gold quality
body of stomach	UBERON:0001161	99.29	gold quality
body of pancreas	UBERON:0001150	99.28	gold quality
right atrium auricular region	UBERON:0006631	99.25	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.22	gold quality
ascending aorta	UBERON:0001496	99.21	gold quality
thoracic aorta	UBERON:0001515	99.21	gold quality
ventricular zone	UBERON:0003053	99.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.21	gold quality
descending thoracic aorta	UBERON:0002345	99.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.20	gold quality
left ovary	UBERON:0002119	99.19	gold quality
endocervix	UBERON:0000458	99.18	gold quality
left coronary artery	UBERON:0001626	99.18	gold quality
metanephros cortex	UBERON:0010533	99.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.17	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	1694.35
E-HCAD-1	yes	46.78
E-HCAD-4	yes	42.34
E-MTAB-9467	yes	30.58
E-CURD-46	yes	26.55
E-CURD-122	yes	23.44
E-MTAB-8410	yes	23.09
E-HCAD-9	yes	17.14
E-MTAB-10042	yes	13.31
E-HCAD-25	yes	7.60
E-MTAB-10553	yes	7.39
E-CURD-88	yes	5.22
E-MTAB-7249	no	8569.12
E-MTAB-9435	no	2388.54
E-CURD-79	no	2368.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting CHCHD2, 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-12118	100.00	65.88	1270
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-4712-3P	98.52	65.39	822
HSA-MIR-8069	97.05	66.79	718
HSA-MIR-6750-3P	96.79	67.50	740
HSA-MIR-6813-3P	95.78	63.78	540
HSA-MIR-7848-3P	95.69	65.00	363

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 59.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Silencing CHCHD2 reduces cellular oxygen consumption and disrupts the assembly and activity of Cytochrome C Oxidase. (PMID:19680543)
• MNRR1 (formerly CHCHD2) is imported to the mitochondrial intermembrane space by a Mia40-mediated pathway, where it binds to cytochrome c oxidase (COX). (PMID:25315652)
• findings establish CHCHD2, a previously uncharacterized small mitochondrial protein with no known homology to the Bcl-2 family, as one of the negative regulators of mitochondria-mediated apoptosis. (PMID:25476776)
• The results of the present study indicated that CHCHD2 may be a novel biomarker for hepatocellular carcinoma and that CREB is important in the transcriptional activation of CHCHD2 by HCV NS2. (PMID:25625293)
• CHCHD2 missense mutations are associated with autosomal dominant Parkinson’s disease. (PMID:25662902)
• CHCHD2 influences mitochondrial and nuclear functions and contributes to the cancer phenotype associated with 7p11.2 amplification in non-small cell lung carcinoma . (PMID:25784717)
• CHCHD2 mutations might not be a common cause of PD in Chinese familial cases. (PMID:26343503)
• The presence of any rare variants in CHCHD2 were more common in Lewy body disease patients with Parkinson’s disease compared to controls. (PMID:26561290)
• CHCHD2 mutations may not account for PD in Canadian patients. (PMID:26639156)
• Autosomal dominant Parkinson’s disease can be caused by CHCHD2 mutations and show that the Pro2Leu variant in CHCHD2 may be a risk factor for sporadic PD in Chinese populations. (PMID:26705026)
• Genetic variants of CHCHD2 do not play a major role in Taiwanese patients with Parkinson disease. (PMID:26725463)
• identified a nonsense variant in exon 3 of CHCHD2 (NM_016139, c.376C > T, p.Gln126X; figure, B) in one German patient with Parkinson disease (PMID:26764027)
• our study suggests that mutations in the CHCHD2 gene are not likely to be a common cause of Parkinson’s disease in Chinese Han population (PMID:27118487)
• The results of this study suggest that CHCHD2 exonic variants are rare among Chinese patients with Parkinson’s disease. (PMID:27269965)
• The results of this study suggest that genetic variants of CHCHD2 may not be a frequent cause of MSA or ALS in our Chinese population. (PMID:27538669)
• We examined the association of rs10043 and Pro2Leu variants in CHCHD2 with Parkinson’s disease. Our study shows a twofold increase of the Pro2Leu variant in CHCHD2 in Parkinson’s disease and meta-analysis of published studies suggests that this may be a risk factor for Parkinson’s disease in Asian populations (PMID:27626775)
• CHCHD2 mutations may be rare in Chinese familial essential tremor patients (PMID:27717833)
• CHCHD2 primes neuroectodermal differentiation of human embryonic stem cell and Human induced pluripotent stem cell by binding and sequestering SMAD4 to the mitochondria, resulting in suppression of the activity of the TGFbeta signaling pathway. (PMID:27810911)
• CHCHD2 gene may not play a major role in our familial Chinese Han essential-tremor and Parkinson’s disease patients. (PMID:27814991)
• CHCHD2 is probably not involved in the etiopathogenesis of PD in a southern Spanish population. (PMID:27839904)
• CHCHD2 mutations might not be the common cause of PD in South Italy. (PMID:27839905)
• A family with Charcot-Marie-Tooth disease type 1A with an exaggerated phenotype harbors a Q112H mutation in MNRR1, located in a domain that is necessary for transcriptional activation by MNRR1 (PMID:27913209)
• Its mutation is not arelevant cause of Parkinson’s disease in Italian population. (PMID:28108040)
• 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)
• These results suggest that the CHCHD2 gene play an important role in Alzheimer’s Disease and Frontotemporal Dementia in a Chinese mainland population. (PMID:29376860)
• It does not play a major role in pathogenesis of mitochondrial myopathy. (PMID:29519717)
• two genetic CHCHD10 disease variants, G66V and P80L, in the mitochondria exhibit faulty interactions with MNRR1 and COX, reducing respiration and increasing reactive oxygen species (ROS), and in the nucleus abrogating transcriptional repression of ORE-containing genes. (PMID:29540477)
• CHCHD2 over-expression plays a role in the occurrence and progression of non-small cell lung cancer and promotes tumor invasion and metastasis (PMID:29643040)
• 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 variants of CHCHD2 are not a common cause of familial PD in Brazilian patients. (PMID:30342766)
• our results suggest CHCHD2 plays a significant role in maintaining mitochondrial contact site and cristae organizing system (MICOS) and mitochondria cristae, whereas Parkinson Disease-associated Q126X and R145Q disrupt MICOS and impair mitochondria function. (PMID:30496485)
• Study provides evidence that MNRR1 regulates multiple genes that function in cell migration and cancer metastasis and is higher in cell lines derived from aggressive breast tumors. (PMID:31046734)
• Study suggests that CHCHD2 is a significant mitochondrial factor that determines alpha-synuclein stability in the etiology of Parkinson disease. (PMID:31600778)
• CHCHD2 is a potential prognostic factor for NSCLC and is associated with HIF-1a expression. (PMID:32054470)
• CHCHD2 harboring Parkinson’s disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2. (PMID:32068847)
• ALS and Parkinson’s disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons. (PMID:32437855)
• CHCHD2 decreases docetaxel sensitivity in breast cancer via activating MMP2. (PMID:32572940)
• Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms. (PMID:33257573)
• Reduced erythrocytic CHCHD2 mRNA is associated with brain pathology of Parkinson’s disease. (PMID:33685516)
• Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2. (PMID:34791217)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	chchd2	ENSDARG00000059304
mus_musculus	Chchd2	ENSMUSG00000070493
rattus_norvegicus	Chchd2l3	ENSRNOG00000051180
rattus_norvegicus	Chchd2	ENSRNOG00000065713
drosophila_melanogaster	Chchd2	FBGN0260747

Paralogs (1): CHCHD10 (ENSG00000250479)

Protein

Protein identifiers

Coiled-coil-helix-coiled-coil-helix domain-containing protein 2 — Q9Y6H1 (reviewed: Q9Y6H1)

Alternative names: Aging-associated gene 10 protein, HCV NS2 trans-regulated protein

All UniProt accessions (1): Q9Y6H1

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor. Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen), as well as normoxia conditions (20% oxygen).

Subunit / interactions. Interacts with RBPJ.

Subcellular location. Nucleus. Mitochondrion. Mitochondrion intermembrane space.

Disease relevance. Parkinson disease 22 (PARK22) [MIM:616710] An autosomal dominant form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The gene represented in this entry may be involved in disease pathogenesis.

Induction. Up-regulated by hypoxia (4% oxygen) (at protein level).

Polymorphism. Mutations in CHCHD2 are rare, and might vary by ethnic origin.

RefSeq proteins (2): NP_001307256, NP_057223* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF06747

UniProt features (23 total): sequence variant 10, compositionally biased region 4, disulfide bond 2, region of interest 2, short sequence motif 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9OYR	ELECTRON MICROSCOPY	2.03
9OYT	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6H1-F1	63.86	0.14

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): 114–144, 124–134

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 180 (showing top): XU_GH1_AUTOCRINE_TARGETS_UP, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_HYPOXIA, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_ELECTRON_TRANSPORT_CHAIN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_STRESS, GOBP_REGULATION_OF_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_CELLULAR_RESPIRATION, GRADE_COLON_AND_RECTAL_CANCER_UP

GO Biological Process (6): mitochondrion organization (GO:0007005), cellular response to oxidative stress (GO:0034599), regulation of generation of precursor metabolites and energy (GO:0043467), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of cellular response to hypoxia (GO:1900037), positive regulation of mitochondrial ATP synthesis coupled electron transport (GO:1905448)

GO Molecular Function (3): sequence-specific DNA binding (GO:0043565), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein localization	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
organelle organization	1
response to oxidative stress	1
cellular response to chemical stress	1
generation of precursor metabolites and energy	1
regulation of metabolic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cellular response to hypoxia	1
regulation of cellular response to stress	1
positive regulation of metabolic process	1
mitochondrial ATP synthesis coupled electron transport	1
regulation of mitochondrial ATP synthesis coupled electron transport	1
DNA binding	1
transcription factor binding	1
binding	1
cytoplasm	1
mitochondrial envelope	1
organelle envelope lumen	1

Protein interactions and networks

STRING

1670 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHCHD2	PLA2G6	O60733	744
CHCHD2	VPS35	Q96QK1	726
CHCHD2	FBXO7	Q9Y3I1	698
CHCHD2	TMEM230	Q96A57	695
CHCHD2	ATP13A2	Q9NQ11	693
CHCHD2	DNAJC13	O75165	690
CHCHD2	VPS13C	Q709C8	671
CHCHD2	PINK1	Q9BXM7	669
CHCHD2	PARK7	Q99497	654
CHCHD2	DNAJC6	O75061	646
CHCHD2	EIF4G1	Q04637	645
CHCHD2	PRKN	O60260	634
CHCHD2	GBA1	P04062	619
CHCHD2	SYNJ1	O43426	619
CHCHD2	CHCHD4	Q8N4Q1	609

IntAct

263 interactions, top by confidence:

A	B	Type	Score
FNTB	FNTA	psi-mi:“MI:0914”(association)	0.960
CHCHD2	POLDIP2	psi-mi:“MI:0915”(physical association)	0.740
POLDIP2	CHCHD2	psi-mi:“MI:0915”(physical association)	0.740
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
GOLGA2	CHCHD2	psi-mi:“MI:0915”(physical association)	0.720
CHCHD2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.720
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
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
LHX4	CHCHD2	psi-mi:“MI:0915”(physical association)	0.670
IKZF3	CHCHD2	psi-mi:“MI:0915”(physical association)	0.670
CHCHD2	LHX4	psi-mi:“MI:0915”(physical association)	0.670
CHCHD2	IKZF3	psi-mi:“MI:0915”(physical association)	0.670
COQ8A	COQ9	psi-mi:“MI:0914”(association)	0.670

BioGRID (279): CHCHD2 (Two-hybrid), CHCHD2 (Two-hybrid), CHCHD2 (Two-hybrid), CHCHD2 (Two-hybrid), CHCHD2 (Two-hybrid), CHCHD2 (Two-hybrid), ADAMTSL4 (Two-hybrid), TRIM54 (Two-hybrid), LHX4 (Two-hybrid), KRT40 (Two-hybrid), INCA1 (Two-hybrid), CHCHD2 (Affinity Capture-MS), CHCHD2 (Co-fractionation), CHCHD2 (Co-fractionation), CHCHD2 (Co-fractionation)

ESM2 similar proteins: A1AFV9, A6TE25, A7ZRR9, A8A4J3, A8APS2, A8GJS8, A9MPX4, A9N5W3, B1ISC0, B1LF30, B2U1E4, B2VGH5, B4T657, B4TI37, B4TVR9, B5BFZ9, B5F680, B5FV55, B5QZ24, B5REE6, B5XU47, B5YR82, B6I408, B7UIU7, C0PYV8, C4ZQV5, C6DIS1, P0ADT2, P0ADT3, P0ADT4, Q03667, Q09254, Q0IHF9, Q0T0M1, Q0TD68, Q10307, Q1CMC8, Q1R6U6, Q31WZ5, Q32BU3

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

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein import	7	15.5×	2e-05
Complex I biogenesis	6	13.1×	3e-04
Respiratory electron transport	10	12.5×	1e-06
Aerobic respiration and respiratory electron transport	10	11.7×	1e-06
Mitochondrial protein degradation	7	10.5×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
ubiquinone biosynthetic process	6	51.5×	8e-07
mitochondrial respiratory chain complex I assembly	5	18.9×	2e-03
proton motive force-driven mitochondrial ATP synthesis	7	16.9×	6e-05
mitochondrial electron transport, NADH to ubiquinone	5	16.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	61
Likely benign	21
Benign	18

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
218882	NM_016139.4(CHCHD2):c.182C>T (p.Thr61Ile)	Pathogenic
218884	NM_016139.4(CHCHD2):c.300+5G>A	Pathogenic

SpliceAI

343 predictions. Top by Δscore:

Variant	Effect	Δscore
7:56101858:AATCC:A	acceptor_loss	1.0000
7:56101859:ATCC:A	acceptor_loss	1.0000
7:56101860:TCC:T	acceptor_loss	1.0000
7:56101861:CCTG:C	acceptor_loss	1.0000
7:56101862:CTGCA:C	acceptor_loss	1.0000
7:56102865:A:AC	donor_gain	1.0000
7:56102866:C:CC	donor_gain	1.0000
7:56102866:C:CG	donor_loss	1.0000
7:56102866:CCG:C	donor_gain	1.0000
7:56102866:CCGT:C	donor_gain	1.0000
7:56103007:GGCTC:G	acceptor_gain	1.0000
7:56103008:GCTC:G	acceptor_gain	1.0000
7:56103009:CTC:C	acceptor_gain	1.0000
7:56103009:CTCC:C	acceptor_gain	1.0000
7:56103010:TC:T	acceptor_gain	1.0000
7:56103010:TCC:T	acceptor_loss	1.0000
7:56103010:TCCT:T	acceptor_gain	1.0000
7:56103011:CC:C	acceptor_gain	1.0000
7:56103012:C:CC	acceptor_gain	1.0000
7:56103021:C:CT	acceptor_gain	1.0000
7:56103022:A:T	acceptor_gain	1.0000
7:56104220:TCCCA:T	donor_loss	1.0000
7:56104221:CCCA:C	donor_loss	1.0000
7:56104222:CCAC:C	donor_loss	1.0000
7:56104223:CA:C	donor_loss	1.0000
7:56104224:ACCTG:A	donor_loss	1.0000
7:56104225:CC:C	donor_loss	1.0000
7:56104265:T:TA	donor_gain	1.0000
7:56104471:CCCGG:C	acceptor_gain	1.0000
7:56104472:CCGG:C	acceptor_gain	1.0000

AlphaMissense

964 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:56104326:G:T	A67D	1.000
7:56104335:G:T	A64D	1.000
7:56104308:C:T	G73E	0.999
7:56104314:G:T	A71D	0.999
7:56104338:G:T	A63E	0.999
7:56102911:C:G	C134S	0.998
7:56102911:C:T	C134Y	0.998
7:56102912:A:T	C134S	0.998
7:56104290:G:T	A79D	0.998
7:56104315:C:G	A71P	0.998
7:56104320:C:T	G69D	0.998
7:56104321:C:G	G69R	0.998
7:56104347:G:T	A60E	0.998
7:56102950:A:G	F121S	0.997
7:56104291:C:G	A79P	0.997
7:56104309:C:G	G73R	0.997
7:56104309:C:T	G73R	0.997
7:56104311:A:T	V72E	0.997
7:56104323:A:T	V68E	0.997
7:56104332:C:T	G65D	0.997
7:56104333:C:G	G65R	0.997
7:56104336:C:G	A64P	0.997
7:56104339:C:G	A63P	0.997
7:56102890:A:G	L141P	0.996
7:56102901:G:C	F137L	0.996
7:56102901:G:T	F137L	0.996
7:56102903:A:G	F137L	0.996
7:56102912:A:G	C134R	0.996
7:56102939:C:G	A125P	0.996
7:56102941:C:G	C124S	0.996

dbSNP variants (sampled 300 via entrez): RS1000020811 (7:56104046 T>C,G), RS1000062782 (7:56107857 G>A,C), RS1000072698 (7:56107589 G>A,C), RS1000282430 (7:56101441 C>A,T), RS1000410429 (7:56102420 G>A), RS1000715876 (7:56101702 A>G), RS1001057228 (7:56105978 C>T), RS1001088436 (7:56106312 C>G,T), RS1001293193 (7:56107902 C>T), RS1001346340 (7:56107256 GAA>G,GAAA), RS1001437987 (7:56101999 T>C,G), RS1001594204 (7:56102102 T>C), RS1001683799 (7:56107644 G>T), RS1002307678 (7:56106558 C>A,T), RS1003059398 (7:56103253 G>T)

Disease associations

OMIM: gene MIM:616244 | disease phenotypes: MIM:616710, MIM:104500

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease 22, autosomal dominant	Strong	Autosomal dominant

Mondo (2): Parkinson disease 22, autosomal dominant (MONDO:0014742), amelogenesis imperfecta (MONDO:0019507)

Orphanet (1): Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000716	Depression
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0001278	Orthostatic hypotension
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002172	Postural instability
HP:0002322	Resting tremor
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0012452	Restless legs

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST007382_34	Plasma free amino acid levels (adjusted for twenty other PFAAs)	5.000000e-21
GCST007385_15	Plasma free amino acid levels	4.000000e-20
GCST009391_2025	Metabolite levels	4.000000e-06
GCST009698_47	Metabolite levels	8.000000e-11
GCST009698_48	Metabolite levels	9.000000e-13
GCST012251_16	Macular telangiectasia type 2	3.000000e-07
GCST012252_7	Macular telangiectasia type 2	6.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005134	amino acid measurement
EFO:0009774	serine measurement
EFO:0010371	lysophosphatidylethanolamine 22:6 measurement
EFO:1002009	macular telangiectasia type 2

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
beauvericin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
abrine	decreases expression	1
MT19c compound	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cisplatin	increases expression	1
Clozapine	affects cotreatment, increases expression	1
Cuprizone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Pesticides	increases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Aflatoxin B1	increases expression	1
Sodium Selenite	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

6 cell lines: 3 induced pluripotent stem cell, 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2U8	Abcam HEK293T CHCHD2 KO	Transformed cell line	Female
CVCL_C1XJ	WCHSCUi001-A	Induced pluripotent stem cell	Male
CVCL_D0EX	FDHSi002-A	Induced pluripotent stem cell	Male
CVCL_SI79	HAP1 CHCHD2 (-) 1	Cancer cell line	Male
CVCL_SI80	HAP1 CHCHD2 (-) 2	Cancer cell line	Male
CVCL_VL50	ZZUi007-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01746121	Not specified	TERMINATED	Amelogenesis Imperfecta
NCT02994862	Not specified	UNKNOWN	E. Max Laminate Veneers With and Without Using Galla Chinnesis as Natural Cross Linking and Remineralizing Agent
NCT03810859	Not specified	UNKNOWN	Non-syndromic Inherited Anomalies of Mineralized Tooth Tissues: a Whole Exome Study to Identify New Pathogenic Variants
NCT04704089	Not specified	RECRUITING	Colorimetric, Ultra-structural and Elemental Comparison of Dental Enamel Defects
NCT04897724	Not specified	UNKNOWN	Clinical Performance of Composites in Patients With Amelogenesis Imperfecta
NCT04927962	Not specified	COMPLETED	Psycho-social Impact of Amelogenesis and Dentinogenesis Imperfecta
NCT05343247	Not specified	COMPLETED	Dental Age Estimation by Different Methods in Patients With Amelogenesis Imperfecta
NCT07250906	Not specified	RECRUITING	Oral Health Related Quality of Life of Children With Amelogenesis Imperfecta