CHCHD4

Summary

CHCHD4 (coiled-coil-helix-coiled-coil-helix domain containing 4, HGNC:26467) is a protein-coding gene on chromosome 3p25.1, encoding Mitochondrial intermembrane space import and assembly protein 40 (Q8N4Q1). Central component of a redox-sensitive mitochondrial intermembrane space import machinery which is required for the biogenesis of respiratory chain complexes. It is a common-essential gene (DepMap: required in 96.4% of cancer cell lines).

CHCHD4, a component of human mitochondria, belongs to a protein family whose members share 6 highly conserved cysteine residues constituting a -CXC-CX(9)C-CX(9)C- motif in the C terminus (Hofmann et al., 2005 [PubMed 16185709]).

Source: NCBI Gene 131474 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 27 total — 2 pathogenic
• Cancer dependency (DepMap): dependent in 96.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_001098502

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26467
Approved symbol	CHCHD4
Name	coiled-coil-helix-coiled-coil-helix domain containing 4
Location	3p25.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ31709, TIMM40, MIA40
Ensembl gene	ENSG00000163528
Ensembl biotype	protein_coding
OMIM	611077
Entrez	131474

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000295767, ENST00000396914, ENST00000420103, ENST00000885073

RefSeq mRNA: 2 — MANE Select: NM_001098502 NM_001098502, NM_144636

CCDS: CCDS2617, CCDS43054

Canonical transcript exons

ENST00000396914 — 3 exons

Exon	Start	End
ENSE00001860999	14124655	14124870
ENSE00001950009	14112077	14113194
ENSE00003680274	14116426	14116524

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 95.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.9851 / max 110.7990, expressed in 1774 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41212	5.2900	1684
41211	4.6950	1525

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	95.56	gold quality
endothelial cell	CL:0000115	92.53	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.32	gold quality
ileal mucosa	UBERON:0000331	92.14	gold quality
kidney epithelium	UBERON:0004819	92.04	gold quality
deltoid	UBERON:0001476	91.85	gold quality
tibialis anterior	UBERON:0001385	91.74	gold quality
myocardium	UBERON:0002349	91.19	gold quality
epithelial cell of pancreas	CL:0000083	90.74	gold quality
quadriceps femoris	UBERON:0001377	90.57	gold quality
heart right ventricle	UBERON:0002080	90.54	gold quality
apex of heart	UBERON:0002098	90.23	gold quality
vastus lateralis	UBERON:0001379	90.13	gold quality
gastrocnemius	UBERON:0001388	89.47	gold quality
skeletal muscle tissue	UBERON:0001134	89.28	gold quality
muscle of leg	UBERON:0001383	89.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.08	gold quality
heart left ventricle	UBERON:0002084	89.04	gold quality
muscle tissue	UBERON:0002385	88.97	gold quality
cardiac ventricle	UBERON:0002082	88.95	gold quality
biceps brachii	UBERON:0001507	88.63	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.44	gold quality
heart	UBERON:0000948	87.22	gold quality
mucosa of transverse colon	UBERON:0004991	87.22	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.93	gold quality
cardiac atrium	UBERON:0002081	86.71	gold quality
right atrium auricular region	UBERON:0006631	86.62	gold quality
esophagus squamous epithelium	UBERON:0006920	86.60	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)

42 targeting CHCHD4, 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-656-3P	100.00	72.15	2788
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-6804-3P	98.72	64.82	852
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-6764-3P	98.44	67.64	1153

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 21)

• biogenesis and function of MIA40 in the mitochondrial intermembrane space is dependent on redox processes involving conserved cysteine residues (PMID:16185709)
• After passage across the translocase of the mitochondrial outer membrane Erv1 interacts via disulfide bonds with Mia40. (PMID:17336303)
• analysis of how mitochondrial biogenesis switches the sorting pathway of the intermembrane space receptor Mia40 (PMID:18779329)
• Catalysis involves a flow of reducing equivalents from the reduced CxC cysteine motif of Mia40 to distal and then proximal CxxC motifs of long-form ALR to the flavin ring and, finally, to cytochrome c or molecular oxygen. (PMID:19397338)
• Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR. (PMID:21383138)
• First group to discover the expression of the human CHCHD4 isoforms and first to call the human gene CHCHD4, and to clone and show the expression of its alternatively expressed CHCHD4 isoforms (CHCHD4.1 and CHCHD4.2). (PMID:22214851)
• mitochondrial localization of MIA40 requires sulfhydryl oxidase ALR in heterologous expression yeast system. (PMID:23186364)
• Import and oxidative folding of proteins are kinetically and functionally coupled and depend on the expression of Mia40, ALR, and the intracellular glutathione pool. (PMID:23676665)
• illustrate a very atypical behaviour for the Mia40 precursor compared to other substrates of the MIA pathway. By contrast, interaction with Erv1 occurs after 5 min of import and relies on a more stringent specificity (PMID:23937629)
• Data indicate that decreased CHCHD4 expression prevents the mitochondrial translocation of p53 while augmenting its nuclear localization and activity. (PMID:24101517)
• Data indicate that poptosis-inducing factor (AIF) controls the mitochondrial import of mitochondrial membrane transport protein CHCHD4. (PMID:26004228)
• In aggregate these data suggest that the Mia40/lfALR system has a broad sequence specificity and that potential substrates may be protected from adventitious oxidation by kinetic sequestration within the mitochondrial IMS. (PMID:26014136)
• our findings suggest that MIA40 reduction contributes to the effects of AIF deficiency on OXPHOS, as it may impact on the correct assembly and maintenance of the respiratory subunits. (PMID:26158520)
• Compared to wild type control littermates, mice with a knockout of CHCHD4 exhibit reduced weight gain when fed a high-fat diet. (PMID:26178476)
• results demonstrate an indispensable role for hMIA40 for the export of Fe-S clusters from mitochondria. (PMID:26275620)
• Data show that the redox state of cytochrome c oxidase assembly protein 17 (Cox17), mitochondrial membrane transport protein Mia40 and superoxide dismutase 1 (SOD1) in the cytoplasm were directly observed with in-cell NMR spectroscopy. (PMID:26589182)
• AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway. (PMID:32105825)
• CHCHD4 (MIA40) and the mitochondrial disulfide relay system. (PMID:33599699)
• Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant. (PMID:37365177)
• [The glutathionylation of the human mitochondrial protein MIA40 regulates ROS homeostasis]. (PMID:38411431)
• CHCHD4 regulates the expression of mitochondrial genes that are essential for tumour cell growth. (PMID:38909850)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	chchd4a	ENSDARG00000033376
mus_musculus	Chchd4	ENSMUSG00000034203
mus_musculus	AU015836	ENSMUSG00000081044
rattus_norvegicus	Chchd4-ps1	ENSRNOG00000022466
rattus_norvegicus	Chchd4l1	ENSRNOG00000032038
rattus_norvegicus	LOC120094797	ENSRNOG00000032860
rattus_norvegicus	Chchd4	ENSRNOG00000069157
caenorhabditis_elegans		WBGENE00008690
caenorhabditis_elegans		WBGENE00018366
caenorhabditis_elegans		WBGENE00022772
caenorhabditis_elegans		WBGENE00022773

Protein

Protein identifiers

Mitochondrial intermembrane space import and assembly protein 40 — Q8N4Q1 (reviewed: Q8N4Q1)

Alternative names: Coiled-coil-helix-coiled-coil-helix domain-containing protein 4

All UniProt accessions (1): Q8N4Q1

UniProt curated annotations — full annotation on UniProt →

Function. Central component of a redox-sensitive mitochondrial intermembrane space import machinery which is required for the biogenesis of respiratory chain complexes. Functions as chaperone and catalyzes the formation of disulfide bonds in substrate proteins, such as COX17, COX19, MICU1 and COA7. Required for the import and folding of small cysteine-containing proteins (small Tim) in the mitochondrial intermembrane space (IMS). Required for the import of COA7 in the IMS. Precursor proteins to be imported into the IMS are translocated in their reduced form into the mitochondria. The oxidized form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with the reduced precursor protein, resulting in oxidation of the precursor protein that now contains an intramolecular disulfide bond and is able to undergo folding in the IMS. Reduced CHCHD4/MIA40 is then reoxidized by GFER/ERV1 via a disulfide relay system. Mediates formation of disulfide bond in MICU1 in the IMS, promoting formation of the MICU1-MICU2 heterodimer that regulates mitochondrial calcium uptake.

Subunit / interactions. Monomer. Can form homooligomers. Interacts with GFER and forms transient disulfide bonds with GFER. Interacts with MICU1. Interacts with COX19 forming transient intermolecular disulfide bridges. Interacts with COA7 through transient intermolecular disulfide bonds. Interacts with AIFM1; the interaction increases in presence of NADH. Interacts with NDUFB10; assists NDUFB10 oxidation, folding and import into mitochondrion.

Subcellular location. Mitochondrion intermembrane space.

Tissue specificity. Expressed in all tissues tested, suggesting an ubiquitous expression.

Post-translational modifications. Forms intrachain disulfide bridges, but exists in different redox states.

Domain organisation. The CHCH domain contains a conserved twin Cys-X(9)-Cys motif which is required for import and stability of MIA40 in mitochondria.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N4Q1-1	1	yes
Q8N4Q1-2	2

RefSeq proteins (2): NP_001091972, NP_653237 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010625	CHCH	Domain
IPR039289	CHCHD4	Family

Pfam: PF06747

UniProt features (29 total): mutagenesis site 8, strand 5, helix 4, disulfide bond 3, region of interest 2, short sequence motif 2, chain 1, domain 1, splice variant 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8VGY	X-RAY DIFFRACTION	2.3
9GQZ	ELECTRON MICROSCOPY	2.36
2K3J	SOLUTION NMR
2L0Y	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N4Q1-F1	75.55	0.38

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 (3): 53–55, 64–97, 74–87

Mutagenesis-validated functional residues (8):

Position	Phenotype
4	no effect on interaction with aifm1.
53–55	no effect on interaction with aifm1.
53	does not strongly affect import and stability of chchd4 in mitochondria; when associated with s-55. no effect on disulfi
55	does not strongly affect import and stability of chchd4 in mitochondria; when associated with s-53. nearly abolishes dis
64	affects import and stability of chchd4 in mitochondria; when associated with s-74.
74	affects import and stability of chchd4 in mitochondria; when associated with s-64. no effect on interaction with aifm1.
87	strongly affects import and stability of chchd4 in mitochondria; when associated with s-97. no effect on interaction wit
97	strongly affects import and stability of chchd4 in mitochondria; when associated with s-87. no effect on interaction wit

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-9609507	Protein localization

MSigDB gene sets: 145 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, TGACCTY_ERR1_Q2, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_MATURATION, WANG_RESPONSE_TO_BEXAROTENE_UP, GOCC_MITOCHONDRIAL_ENVELOPE, TGANTCA_AP1_C, GOBP_PROTEIN_FOLDING, PPAR_DR1_Q2, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PROTEIN_TRANSMEMBRANE_TRANSPORT, TAATGTG_MIR323

GO Biological Process (6): mitochondrial respiratory chain complex assembly (GO:0033108), protein import into mitochondrial intermembrane space (GO:0045041), protein maturation (GO:0051604), protein import into the intermembrane space via the disulfide relay system (GO:0160203), protein transport (GO:0015031), obsolete establishment of protein localization to mitochondrion (GO:0072655)

GO Molecular Function (3): protein-disulfide reductase activity (GO:0015035), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758)

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
mitochondrion	1
mitochondrion organization	1
protein-containing complex assembly	1
mitochondrial protein import pathway	1
gene expression	1
protein metabolic process	1
protein import into mitochondrial intermembrane space	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
disulfide oxidoreductase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial envelope	1
organelle envelope lumen	1

Protein interactions and networks

STRING

1444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHCHD4	TIMM10	P62072	980
CHCHD4	GFER	P55789	966
CHCHD4	TIMM8A	O60220	931
CHCHD4	COX17	Q14061	904
CHCHD4	MICU1	Q9BPX6	886
CHCHD4	TIMM9	Q9Y5J7	883
CHCHD4	ATP23	Q9Y6H3	871
CHCHD4	TIMM13	P62206	777
CHCHD4	COX19	Q49B96	728
CHCHD4	TOMM40	O96008	726
CHCHD4	TIMM50	Q3ZCQ8	718
CHCHD4	SAMM50	Q9Y512	717
CHCHD4	TIMM17A	Q99595	713
CHCHD4	TIMM10B	Q9Y5J6	711
CHCHD4	TOMM70	O94826	705

IntAct

70 interactions, top by confidence:

A	B	Type	Score
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
CHCHD4	SSNA1	psi-mi:“MI:0914”(association)	0.640
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
UQCRH	COX7A2L	psi-mi:“MI:0914”(association)	0.640
CHCHD4	MICU1	psi-mi:“MI:0915”(physical association)	0.580
ERBB3	AIFM1	psi-mi:“MI:0914”(association)	0.570
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
ZNF581	DMWD	psi-mi:“MI:0914”(association)	0.530
CHCHD4	ENSA	psi-mi:“MI:0914”(association)	0.530
TOR1AIP1	TXN	psi-mi:“MI:0914”(association)	0.530
FANCD2OS	CNOT1	psi-mi:“MI:0914”(association)	0.530
AIFM1	HAX1	psi-mi:“MI:0914”(association)	0.420
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
AIFM1	SEC16A	psi-mi:“MI:2364”(proximity)	0.420
Tubb4b	MGST3	psi-mi:“MI:0915”(physical association)	0.400
HADHB	CHCHD4	psi-mi:“MI:0915”(physical association)	0.370
Aifm1	HMGB1	psi-mi:“MI:0914”(association)	0.350
TOR1AIP1	USP1	psi-mi:“MI:0914”(association)	0.350
	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
SMARCB1		psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
NEK4	QSOX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (149): CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), CHCHD4 (Proximity Label-MS), CHCHD4 (Proximity Label-MS), CHCHD4 (Proximity Label-MS)

ESM2 similar proteins: A6ZRR2, A6ZT54, B2GUV7, B3LP25, B3LSR0, C7GJZ2, C7GTE8, C8Z9U3, C8ZG55, E7KDM2, E7KPJ0, E7LVH4, E7NIP0, E7Q4T7, O04209, O42932, O60841, O94030, O94356, P00127, P0C1D2, P0CM68, P0CM69, P34618, P36046, P38845, P53885, P87059, Q05D44, Q10195, Q19972, Q1MTR4, Q4IK03, Q4P8D2, Q5BJN5, Q5RDE1, Q6BSK8, Q6CSA1, Q6FL84, Q6FW26

Diamond homologs: O94030, P0C1D2, P0CM68, P0CM69, P34415, P36046, P87059, Q2KHZ4, Q2USJ2, Q4IK03, Q4P8D2, Q4WGL2, Q5BJN5, Q63ZK1, Q6BSK8, Q6CSA1, Q6DEI8, Q6FW26, Q6NU12, Q6PBC3, Q757A5, Q7S3S2, Q7XKI7, Q8GYJ4, Q8N4Q1, Q8VEA4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 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	5	15.6×	2e-03
Complex I biogenesis	5	15.3×	2e-03
Respiratory electron transport	8	14.1×	2e-05
Aerobic respiration and respiratory electron transport	6	9.8×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven mitochondrial ATP synthesis	5	18.8×	2e-03
aerobic respiration	5	17.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	20
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
148876	GRCh38/hg38 3p26.3-24.3(chr3:32241-20334387)x3	Pathogenic
4795219	NM_001098502.2(CHCHD4):c.5C>T (p.Ser2Phe)	Pathogenic

SpliceAI

751 predictions. Top by Δscore:

Variant	Effect	Δscore
3:14116419:CACT:C	donor_loss	1.0000
3:14116420:ACTC:A	donor_loss	1.0000
3:14116421:CTCA:C	donor_loss	1.0000
3:14116422:TCA:T	donor_loss	1.0000
3:14116423:C:CG	donor_loss	1.0000
3:14116424:ACCAT:A	donor_loss	1.0000
3:14116425:CCATG:C	donor_gain	1.0000
3:14116524:CCTAG:C	acceptor_gain	1.0000
3:14116528:G:GC	acceptor_gain	1.0000
3:14116424:A:AC	donor_gain	0.9900
3:14116424:AC:A	donor_gain	0.9900
3:14116425:C:CC	donor_gain	0.9900
3:14116425:CC:C	donor_gain	0.9900
3:14116520:CTTCC:C	acceptor_gain	0.9900
3:14116521:TTCC:T	acceptor_gain	0.9900
3:14116523:CC:C	acceptor_gain	0.9900
3:14116524:CC:C	acceptor_loss	0.9900
3:14116525:C:CC	acceptor_gain	0.9900
3:14116526:T:A	acceptor_loss	0.9900
3:14116528:G:C	acceptor_gain	0.9900
3:14116532:T:C	acceptor_gain	0.9900
3:14116532:T:TC	acceptor_gain	0.9900
3:14116540:C:CT	acceptor_gain	0.9900
3:14119153:T:TA	donor_gain	0.9900
3:14124657:T:TA	donor_gain	0.9900
3:14124690:C:A	donor_gain	0.9900
3:14116417:GTCAC:G	donor_loss	0.9800
3:14116418:TCACT:T	donor_loss	0.9800
3:14116522:TCC:T	acceptor_gain	0.9800
3:14116523:CCC:C	acceptor_gain	0.9800

AlphaMissense

948 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:14113112:A:C	F68L	1.000
3:14113112:A:T	F68L	1.000
3:14113114:A:G	F68L	1.000
3:14113163:C:A	W51C	1.000
3:14113163:C:G	W51C	1.000
3:14113043:G:C	F91L	0.999
3:14113043:G:T	F91L	0.999
3:14113045:A:G	F91L	0.999
3:14113056:C:T	C87Y	0.999
3:14113091:G:C	F75L	0.999
3:14113091:G:T	F75L	0.999
3:14113093:A:G	F75L	0.999
3:14113100:A:C	F72L	0.999
3:14113100:A:T	F72L	0.999
3:14113101:A:G	F72S	0.999
3:14113102:A:G	F72L	0.999
3:14113109:C:A	K69N	0.999
3:14113109:C:G	K69N	0.999
3:14113113:A:C	F68C	0.999
3:14113113:A:G	F68S	0.999
3:14113125:C:T	C64Y	0.999
3:14113152:C:T	C55Y	0.999
3:14113157:G:C	C53W	0.999
3:14113158:C:G	C53S	0.999
3:14113158:C:T	C53Y	0.999
3:14113159:A:G	C53R	0.999
3:14113159:A:T	C53S	0.999
3:14113164:C:G	W51S	0.999
3:14113165:A:G	W51R	0.999
3:14113165:A:T	W51R	0.999

dbSNP variants (sampled 300 via entrez): RS1000484109 (3:14126459 T>A), RS1000595584 (3:14120500 C>T), RS1000747794 (3:14114293 C>T), RS1000800295 (3:14114544 CA>C), RS1001095677 (3:14115411 A>G), RS1001100012 (3:14126171 T>G), RS1001117751 (3:14124113 T>A), RS1001327651 (3:14117842 G>A), RS1001394532 (3:14122465 A>G), RS1001753280 (3:14115596 G>T), RS1002116966 (3:14122736 G>A), RS1002268813 (3:14115801 T>C), RS1002596133 (3:14123625 A>G), RS1002727904 (3:14116113 G>A), RS1002739797 (3:14116707 C>A,G)

Disease associations

OMIM: gene MIM:611077 | disease phenotypes:

GenCC curated gene-disease

Mondo (3): hypoglycemia (MONDO:0004946), fetal growth restriction (MONDO:0005030), lactic acidosis (MONDO:0006040)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000140	Acidosis, Lactic	C18.452.076.176.180
D005317	Fetal Growth Retardation	C12.050.703.277.370; C16.300.390; C23.550.393.450
D007003	Hypoglycemia	C18.452.394.984

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
Valproic Acid	affects cotreatment, increases expression	6
trichostatin A	affects cotreatment, increases expression	3
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic 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
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Hydrogen Peroxide	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00490893	PHASE4	TERMINATED	Hypoglycemia Counterregulation and Symptom Perception With Insulin Detemir
NCT00641407	PHASE4	COMPLETED	Bedtime Insulins and Oral Antihyperglycemic Drugs in Type 2 Diabetes
NCT00766441	PHASE4	TERMINATED	Sitagliptin Versus Sulphonylurea in Type 2 Diabetes During Ramadan
NCT01013402	PHASE4	COMPLETED	Investigating the Accuracy of the Home Glucose Monitors in Hypoglycemia
NCT01147276	PHASE4	COMPLETED	Vildagliptin and the Glucagon Response to Hypoglycemia in Type 1 Diabetes
NCT01387477	PHASE4	WITHDRAWN	Lactate to Treat Hypoglycemia
NCT01841359	PHASE4	COMPLETED	Pramlintide (Symlin) for the Treatment of Hypoglycemia Following Gastric Bypass Surgery
NCT02007278	PHASE4	COMPLETED	Glycemic Excursions in Type 2 Diabetic Patients With Vildagliptin and Metformin Versus Vildagliptin and Glimepiride
NCT02336438	PHASE4	COMPLETED	The Effect of Glucomannan Soluble Fiber on Glucose Homeostasis in Patients With Roux En Y (RNY) Gastric Bypass Surgery
NCT02527993	PHASE4	COMPLETED	Treatment of Hypoglycemia Following Gastric Bypass Surgery
NCT02578498	PHASE4	COMPLETED	Glucagon Efficiency After High and Low Carbohydrate Diet
NCT02881060	PHASE4	COMPLETED	The Late Effects of Ethanol Intake on the Glucose Response to Subcutaneous Glucagon in Type 1 Diabetes
NCT03429946	PHASE4	COMPLETED	Hypoglycemia and Autonomic Nervous System Function-B
NCT03608163	PHASE4	TERMINATED	Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)
NCT04053712	PHASE4	COMPLETED	Dual-hormone Closed-loop Glucose Control in Type 1 Diabetes
NCT06986603	PHASE4	ACTIVE_NOT_RECRUITING	Glucagon Dose-Response in Patients With Post-Bariatric Hypoglycemia
NCT00347867	PHASE4	UNKNOWN	Viagra for the Treatment of IUGR
NCT00909974	PHASE4	COMPLETED	Effect of Prenatal Nutritional Supplementation on Birth Outcome in Hounde District, Burkina Faso
NCT00554281	PHASE3	COMPLETED	Using Glucose Sensors to Prevent Hypoglycemia
NCT00804297	PHASE3	COMPLETED	Octreotide for the Treatment of Sulfonylurea-Associated Hypoglycemia
NCT02171130	PHASE3	COMPLETED	Clinical Usability of Intranasal Glucagon in Treatment of Hypoglycemia
NCT02402933	PHASE3	COMPLETED	Clinical Usability of Nasal Glucagon in Treatment of Hypoglycemia in Children and Adolescents
NCT02656069	PHASE3	COMPLETED	Safety and Efficacy of G-Pen Compared to Lilly Glucagon for Hypoglycemia Rescue in Adult Type 1 Diabetics
NCT03216226	PHASE3	COMPLETED	A Trial to Evaluate the Immunogenicity of Dasiglucagon and GlucaGen in Patients With Type 1 Diabetes Mellitus
NCT03378635	PHASE3	COMPLETED	A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects
NCT03439072	PHASE3	COMPLETED	G-Pen™ Compared to Lilly Glucagon for Hypoglycemia Rescue in Adults With Type 1 Diabetes
NCT03667053	PHASE3	COMPLETED	Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children
NCT03688711	PHASE3	COMPLETED	Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Subjects With T1DM
NCT03738865	PHASE3	COMPLETED	G-Pen Compared to Glucagen Hypokit for Severe Hypoglycemia Rescue in Adults With Type 1 Diabetes
NCT03802942	PHASE3	UNKNOWN	Prevention of Hypoglycemia Among Diabetes Patients Admitted to Internal Medicine Departments With Nutritional Care
NCT03895697	PHASE3	COMPLETED	A Trial to Compare the Efficacy and Safety of 2 Different Batches of Subcutaneous Dasiglucagon in Patients With T1DM
NCT04786262	PHASE3	RECRUITING	A Safety, Tolerability, and Efficacy Study of VX-880 in Participants With Type 1 Diabetes
NCT05378672	PHASE3	COMPLETED	A Study to Inv. Safety, Efficacy & PD of Dasiglucagon as Hypoglycemia Rescue Therapy in Children <6 Years With T1D
NCT00434772	PHASE2	COMPLETED	Glucagon in the Treatment of Hypoglycemia in Newborn Infants of Diabetic Mothers
NCT00446264	PHASE2	COMPLETED	Islet Allotransplantation With Steroid Free Immunosuppression
NCT00678145	PHASE2	TERMINATED	Mechanisms of Hypoglycemia Associated Autonomic Failure
NCT00798590	PHASE2	TERMINATED	The Efficacy of Glucagon Like Peptide (GLP) - 1(7-36) Amide for Glycemic Control in Critically Ill Patients
NCT01556594	PHASE2	COMPLETED	Safety and Efficacy of a Novel Glucagon Formulation in Type 1 Diabetic Patients Following Insulin-induced Hypoglycemia
NCT01972152	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of G-Pen(TM) (Glucagon Injection) to Treat Severe Hypoglycemia
NCT02081001	PHASE2	COMPLETED	PK/PD Study With G-Pump (Glucagon Infusion) in T1DM Patients