IDH3A

Summary

IDH3A (isocitrate dehydrogenase (NAD(+)) 3 catalytic subunit alpha, HGNC:5384) is a protein-coding gene on chromosome 15q25.1, encoding Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (P50213). Catalytic subunit of the enzyme which catalyzes the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. It is a selective cancer dependency (DepMap: 38.2% of cell lines).

Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the alpha subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase.

Source: NCBI Gene 3419 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinitis pigmentosa 90 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 296 total — 13 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 38.2% of screened cell lines
• MANE Select transcript: NM_005530

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5384
Approved symbol	IDH3A
Name	isocitrate dehydrogenase (NAD(+)) 3 catalytic subunit alpha
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166411
Ensembl biotype	protein_coding
OMIM	601149
Entrez	3419

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 20 protein_coding, 8 nonsense_mediated_decay, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000299518, ENST00000557826, ENST00000557960, ENST00000558016, ENST00000558509, ENST00000558535, ENST00000558554, ENST00000558602, ENST00000558605, ENST00000558933, ENST00000559106, ENST00000559186, ENST00000559205, ENST00000559803, ENST00000559865, ENST00000559881, ENST00000559889, ENST00000560396, ENST00000560414, ENST00000560667, ENST00000560770, ENST00000561279, ENST00000561366, ENST00000629769, ENST00000889871, ENST00000889872, ENST00000889873, ENST00000889874, ENST00000889875, ENST00000889876, ENST00000889877, ENST00000889878, ENST00000921734, ENST00000943584

RefSeq mRNA: 1 — MANE Select: NM_005530 NM_005530

CCDS: CCDS10297

Canonical transcript exons

ENST00000299518 — 11 exons

Exon	Start	End
ENSE00001921663	78168922	78171945
ENSE00003471134	78157548	78157631
ENSE00003506318	78164992	78165076
ENSE00003575510	78149362	78149430
ENSE00003607827	78163507	78163609
ENSE00003635218	78166150	78166302
ENSE00003663216	78163716	78163780
ENSE00003688101	78155213	78155275
ENSE00003784210	78161581	78161768
ENSE00003785231	78160092	78160206
ENSE00003787166	78162234	78162367

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.6333 / max 315.7795, expressed in 1811 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147887	29.6333	1811

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right atrium auricular region	UBERON:0006631	98.46	gold quality
heart right ventricle	UBERON:0002080	98.31	gold quality
heart left ventricle	UBERON:0002084	97.93	gold quality
cardiac ventricle	UBERON:0002082	97.90	gold quality
adrenal tissue	UBERON:0018303	97.57	gold quality
rectum	UBERON:0001052	97.36	gold quality
heart	UBERON:0000948	97.24	gold quality
apex of heart	UBERON:0002098	97.22	gold quality
cardiac atrium	UBERON:0002081	97.12	gold quality
prefrontal cortex	UBERON:0000451	96.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.91	gold quality
gastrocnemius	UBERON:0001388	96.81	gold quality
biceps brachii	UBERON:0001507	96.66	gold quality
nucleus accumbens	UBERON:0001882	96.41	gold quality
right adrenal gland cortex	UBERON:0035827	96.39	gold quality
muscle of leg	UBERON:0001383	96.38	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.37	gold quality
left adrenal gland	UBERON:0001234	96.32	gold quality
left adrenal gland cortex	UBERON:0035825	96.30	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.29	gold quality
right adrenal gland	UBERON:0001233	96.17	gold quality
transverse colon	UBERON:0001157	96.15	gold quality
adrenal gland	UBERON:0002369	96.12	gold quality
colonic mucosa	UBERON:0000317	96.09	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.08	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.08	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.05	gold quality
cerebellar hemisphere	UBERON:0002245	95.89	gold quality
cerebellar cortex	UBERON:0002129	95.88	gold quality
mucosa of transverse colon	UBERON:0004991	95.88	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	15.41
E-MTAB-9067	yes	13.19
E-CURD-122	yes	12.39
E-MTAB-8498	yes	12.38
E-MTAB-9801	yes	6.72
E-ANND-3	yes	5.66
E-MTAB-6678	yes	4.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting IDH3A, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-6505-5P	99.73	69.25	1595

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 38.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• for IDH, a normal alpha subunit is required for catalytic activity and alpha-Arg88 likely participates in the isocitrate site, whereas the beta and gamma subunits have roles in the nucleotide functions of this allosteric enzyme (PMID:14555658)
• active sites of the human NAD-IDH are shared between alpha and gamma subunits and between alpha and beta subunits (PMID:16737955)
• Asp181 is essential for nicotinamide-adenine dinucleotide (NAD)-specific IDH alpha subunit catalysis and may also facilitate the binding of substrates. (PMID:17432878)
• The silencing of IDH3a significantly delayed tumor growth by suppressing the HIF-1-mediated Warburg effect and angiogenesis. (PMID:25531325)
• IDH3alpha is elevated in glioblastoma patient samples compared to normal brain tissue and promotes glioblastoma progression in orthotopic glioma mouse models. On molecular levels, IDH3alpha ablation reduces TCA cycle turnover and shunts energy metabolism. In addition, IDH3alpha affects one-carbon metabolism and regulates nucleotide production as well as DNA methylation through effect on cSHMT. (PMID:30613765)
• This study highlights the importance of including this rarely-mutated gene in the molecular diagnostic set-ups for inherited retinal degenerations, and further delineates the phenotypic spectrum elicited by mutations in IDH3A. (PMID:31012789)
• Association between IDH mutational status and tumor-associated epilepsy or venous thromboembolism in patients with grade II and III astrocytoma. (PMID:34269949)
• Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia. (PMID:35463978)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	idh3a	ENSDARG00000030278
mus_musculus	Idh3a	ENSMUSG00000032279
rattus_norvegicus	Idh3a	ENSRNOG00000010277
drosophila_melanogaster	Idh3a	FBGN0027291
drosophila_melanogaster	CG32026	FBGN0052026
caenorhabditis_elegans	idha-1	WBGENE00009664

Paralogs (2): IDH3G (ENSG00000067829), IDH3B (ENSG00000101365)

Protein

Protein identifiers

Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial — P50213 (reviewed: P50213)

Alternative names: Isocitric dehydrogenase subunit alpha, NAD(+)-specific ICDH subunit alpha

All UniProt accessions (14): A0A0G2JL95, P50213, H0YKD0, H0YL05, H0YL72, H0YLF8, H0YLI6, H0YM46, H0YM64, H0YMU3, H0YMY5, H0YNF5, H0YNF8, Q68D72

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the enzyme which catalyzes the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.

Subunit / interactions. Heterooligomer of subunits alpha (IDH3A), beta (IDH3B), and gamma (IDH3G) in the apparent ratio of 2:1:1. The heterodimer containing one IDH3A and one IDH3B subunit and the heterodimer containing one IDH3A and one IDH3G subunit assemble into a heterotetramer (which contains two subunits of IDH3A, one of IDH3B and one of IDH3G) and further into the heterooctamer.

Subcellular location. Mitochondrion.

Disease relevance. Retinitis pigmentosa 90 (RP90) [MIM:619007] A form of retinitis pigmentosa, a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. RP90 is an autosomal recessive form. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The heterotetramer and the heterodimer composed of IDH3A and IDH3G subunits can be allosterically activated by citrate (CIT) or/and ADP, and the two activators can act independently or synergistically. The heterodimer composed of IDH3A and IDH3B subunits cannot be allosterically regulated and the allosteric regulation of the heterotetramer is through the IDH3G subunit and not the IDH3B subunit. The IDH3G subunit contains the allosteric site which consists of a CIT-binding site and an ADP-binding site, and the binding of CIT and ADP causes conformational changes at the allosteric site which are transmitted to the active site in the catalytic subunit (IDH3A) through a cascade of conformational changes at the heterodimer interface, leading to stabilization of the isocitrate-binding at the active site and thus activation of the enzyme. ATP can activate the heterotetramer and the heterodimer composed of IDH3A and IDH3G subunits at low concentrations but inhibits their activities at high concentrations, whereas ATP exhibits only inhibitory effect on the heterodimer composed of IDH3A and IDH3B subunits.

Cofactor. Divalent metal cations; Mn(2+) or Mg(2+). Activity higher in presence of Mn(2+) than of Mg(2+). Binds 1 Mg(2+) or Mn(2+) ion per subunit.

Similarity. Belongs to the isocitrate and isopropylmalate dehydrogenases family.

Isoforms (2)

UniProt ID	Names	Canonical?
P50213-1	1	yes
P50213-2	2

RefSeq proteins (1): NP_005521* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004434	Isocitrate_DH_NAD	Family
IPR019818	IsoCit/isopropylmalate_DH_CS	Conserved_site
IPR024084	IsoPropMal-DH-like_dom	Domain

Pfam: PF00180

Enzyme classification (BRENDA):

• EC 1.1.1.41 — isocitrate dehydrogenase (NAD+) (BRENDA: 54 organisms, 76 substrates, 122 inhibitors, 162 Km, 90 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NAD+	0.004–20.65	60
ISOCITRATE	0.009–41	37
NADP+	0.0082–8.2	27
D-ISOCITRATE	0.09–62.2	20
DL-ISOCITRATE	0.002–0.385	6
D,L-ISOCITRATE	0.03–0.45	3
MN2+	0.22–0.39	2
HOMOISOCITRATE	0.0183	1

Catalyzed reactions (Rhea), 1 shown:

• D-threo-isocitrate + NAD(+) = 2-oxoglutarate + CO2 + NADH (RHEA:23632)

UniProt features (67 total): strand 18, helix 15, sequence variant 8, mutagenesis site 7, modified residue 6, binding site 6, turn 2, site 2, transit peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
6L59	X-RAY DIFFRACTION	2.25
6L57	X-RAY DIFFRACTION	2.3
5GRI	X-RAY DIFFRACTION	2.31
5YVT	X-RAY DIFFRACTION	2.4
5GRF	X-RAY DIFFRACTION	2.5
8GRH	X-RAY DIFFRACTION	2.51
5GRE	X-RAY DIFFRACTION	2.65
8GRD	X-RAY DIFFRACTION	2.7
8GRG	X-RAY DIFFRACTION	2.7
5GRL	X-RAY DIFFRACTION	2.79
5GRH	X-RAY DIFFRACTION	2.8
8GRU	X-RAY DIFFRACTION	2.85
8GRB	X-RAY DIFFRACTION	2.85
6KDE	X-RAY DIFFRACTION	3
6KDY	X-RAY DIFFRACTION	3.02
6KDF	X-RAY DIFFRACTION	3.05
6KE3	X-RAY DIFFRACTION	3.31
7CE3	X-RAY DIFFRACTION	3.47
8GS5	X-RAY DIFFRACTION	4.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50213-F1	90.83	0.85

Functional residue map

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

Catalytic / active sites (2): 153 (critical for catalysis); 200 (critical for catalysis)

Ligand- & substrate-binding residues (6): 115; 125; 146; 233; 257; 261

Post-translational modifications (6): 77, 101, 223, 343, 343, 350

Mutagenesis-validated functional residues (7):

Position	Phenotype
152	no significant effect on the activation of the heterodimer composed of idh3a and idh3g subunits by citrate and adp.
153	complete loss of activity of the heterotetramer, heterodimer composed of idh3a and idh3b subunits and the heterodimer co
169	significantly impairs the activation of the heterodimer composed of idh3a and idh3g subunits by citrate and adp.
200	significantly impairs the activation of the heterodimer composed of idh3a and idh3g subunits by citrate.
202	significantly impairs the activation of the heterodimer composed of idh3a and idh3g subunits by citrate.
208	complete loss of the activation of the heterodimer composed of idh3a and idh3g subunits by citrate and adp.
255	significantly impairs the activation of the heterodimer composed of idh3a and idh3g subunits by citrate and adp.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 307 (showing top): ELVIDGE_HYPOXIA_DN, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, TGACCTY_ERR1_Q2, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_TRICARBOXYLIC_ACID_METABOLIC_PROCESS, RAHMAN_TP53_TARGETS_PHOSPHORYLATED, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, MORF_PRKDC, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, DOUGLAS_BMI1_TARGETS_UP, ZHANG_BREAST_CANCER_PROGENITORS_UP, MORF_AATF, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS, ZHU_CMV_24_HR_UP

GO Biological Process (3): carbohydrate metabolic process (GO:0005975), tricarboxylic acid cycle (GO:0006099), isocitrate metabolic process (GO:0006102)

GO Molecular Function (7): magnesium ion binding (GO:0000287), isocitrate dehydrogenase (NAD+) activity (GO:0004449), NAD binding (GO:0051287), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), isocitrate dehydrogenase complex (NAD+) (GO:0045242)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	2
intracellular membrane-bounded organelle	2
aerobic respiration	1
tricarboxylic acid metabolic process	1
secondary alcohol metabolic process	1
metal ion binding	1
isocitrate dehydrogenase [NAD(P)+] activity	1
adenyl nucleotide binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on CH-OH group of donors	1
cation binding	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
tricarboxylic acid cycle heteromeric enzyme complex	1
oxidoreductase complex	1

Protein interactions and networks

STRING

2992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IDH3A	IDH3G	P51553	967
IDH3A	IDH2	P48735	954
IDH3A	IDH3B	O43837	933
IDH3A	KIAA1217	Q5T5P2	824
IDH3A	IDH1	O75874	793
IDH3A	OGDH	Q02218	772
IDH3A	ACO2	Q99798	771
IDH3A	MDH2	P40926	732
IDH3A	NNT	Q13423	714
IDH3A	PDHB	P11177	710
IDH3A	SUCLA2	Q9P2R7	699
IDH3A	SDHA	P31040	688
IDH3A	SUCLG1	P53597	669
IDH3A	CS	O75390	667
IDH3A	SDHB	P21912	640

IntAct

72 interactions, top by confidence:

A	B	Type	Score
IDH3A	IDH3G	psi-mi:“MI:0407”(direct interaction)	0.820
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
IDH3A	IDH3B	psi-mi:“MI:0915”(physical association)	0.690
IDH3A	IDH3B	psi-mi:“MI:0914”(association)	0.690
	IDH3A	psi-mi:“MI:0407”(direct interaction)	0.610
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IDH3A	SHMT1	psi-mi:“MI:0915”(physical association)	0.460
SHMT1	IDH3A	psi-mi:“MI:0915”(physical association)	0.460
SHMT1	IDH3A	psi-mi:“MI:0403”(colocalization)	0.460
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
gag-pol	EIF3F	psi-mi:“MI:0914”(association)	0.460
	IDH3A	psi-mi:“MI:0407”(direct interaction)	0.440
	IDH3B	psi-mi:“MI:0915”(physical association)	0.400
MBNL1	IDH3A	psi-mi:“MI:0915”(physical association)	0.370
IDH3A	RAB4A	psi-mi:“MI:0915”(physical association)	0.370
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350

BioGRID (151): IDH3A (Affinity Capture-MS), IDH3A (Affinity Capture-MS), IDH3A (Affinity Capture-MS), IDH3B (Affinity Capture-MS), RDH13 (Affinity Capture-MS), IDH3G (Affinity Capture-MS), ABCC1 (Co-fractionation), ABCC3 (Co-fractionation), ACO2 (Co-fractionation), ACTN4 (Co-fractionation), ATP2B1 (Co-fractionation), CCT8 (Co-fractionation), HDHD1 (Co-fractionation), IDH1 (Co-fractionation), IDH3A (Co-fractionation)

ESM2 similar proteins: A1Z9J4, A2XNR6, E9AD19, F6HDM2, O16228, O48881, O74197, O82662, P00937, P09556, P13995, P18155, P21264, P29696, P35914, P40386, P41563, P50213, P53588, P55195, P55880, P56471, P90994, P93032, Q01637, Q0P5C2, Q10356, Q148D5, Q3MHX5, Q46948, Q4R517, Q55AI5, Q5R678, Q5R9E1, Q5ZKA5, Q6K9N6, Q75LJ3, Q84LB6, Q869S7, Q8HXZ6

Diamond homologs: A0A5A4WIX0, D4GU92, K0E689, O29610, O29627, O67480, O81796, O94230, P08200, P29102, P29696, P33197, P39126, P41560, P41563, P50213, P50214, P56063, P56471, P65099, P73960, P80046, P93032, P93832, P96318, P99167, Q00412, Q02NB5, Q1MA50, Q1RJU4, Q21CS1, Q28480, Q2K2V0, Q2NVW4, Q2P762, Q2RV53, Q31B91, Q31N34, Q39Y29, Q3KF21

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IDH3A	“form complex”	IDH	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	8
Uncertain significance	111
Likely benign	133
Benign	21

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1068937	NM_005530.3(IDH3A):c.46del (p.Ala16fs)	Pathogenic
1446597	NM_005530.3(IDH3A):c.17G>A (p.Trp6Ter)	Pathogenic
2026541	NM_005530.3(IDH3A):c.373C>T (p.Arg125Ter)	Pathogenic
2065182	NM_005530.3(IDH3A):c.592del (p.Val198fs)	Pathogenic
2878708	NM_005530.3(IDH3A):c.81dup (p.Thr28fs)	Pathogenic
3248805	NM_005530.3(IDH3A):c.904_916del (p.Ala302fs)	Pathogenic
4734926	NM_005530.3(IDH3A):c.287_288del (p.Lys96fs)	Pathogenic
977468	NM_005530.3(IDH3A):c.716T>C (p.Met239Thr)	Pathogenic
977469	NM_005530.3(IDH3A):c.403del (p.Thr135fs)	Pathogenic
977470	NM_005530.3(IDH3A):c.524C>T (p.Ala175Val)	Pathogenic
977471	NM_005530.3(IDH3A):c.463G>T (p.Gly155Ter)	Pathogenic
977472	NM_005530.3(IDH3A):c.946C>T (p.Arg316Cys)	Pathogenic
977473	NM_005530.3(IDH3A):c.612G>A (p.Met204Ile)	Pathogenic
1067058	NM_005530.3(IDH3A):c.714+1G>A	Likely pathogenic
1067070	NM_005530.3(IDH3A):c.715-1G>C	Likely pathogenic
1467972	NM_005530.3(IDH3A):c.27+2T>C	Likely pathogenic
1480640	NM_005530.3(IDH3A):c.779+1G>A	Likely pathogenic
2012441	NM_005530.3(IDH3A):c.611+2T>G	Likely pathogenic
2836505	NM_005530.3(IDH3A):c.90+1G>A	Likely pathogenic
3654994	NM_005530.3(IDH3A):c.864+1G>C	Likely pathogenic
4715378	NM_005530.3(IDH3A):c.27+2T>G	Likely pathogenic

SpliceAI

2057 predictions. Top by Δscore:

Variant	Effect	Δscore
15:78157632:G:GG	donor_gain	1.0000
15:78161579:AGGCC:A	acceptor_loss	1.0000
15:78161766:GTG:G	donor_gain	1.0000
15:78161767:TGG:T	donor_loss	1.0000
15:78161770:T:A	donor_loss	1.0000
15:78162231:CAGAT:C	acceptor_loss	1.0000
15:78162232:A:AG	acceptor_gain	1.0000
15:78162232:AGATT:A	acceptor_gain	1.0000
15:78162233:G:GA	acceptor_gain	1.0000
15:78162233:GA:G	acceptor_gain	1.0000
15:78162233:GAT:G	acceptor_gain	1.0000
15:78162233:GATT:G	acceptor_gain	1.0000
15:78162233:GATTG:G	acceptor_gain	1.0000
15:78162363:ATCAT:A	donor_gain	1.0000
15:78162364:TCAT:T	donor_gain	1.0000
15:78162366:ATGTG:A	donor_loss	1.0000
15:78162367:TG:T	donor_loss	1.0000
15:78162368:G:GG	donor_gain	1.0000
15:78162368:GTG:G	donor_loss	1.0000
15:78163606:GAAT:G	donor_gain	1.0000
15:78163710:TTGTA:T	acceptor_loss	1.0000
15:78163711:TGTAG:T	acceptor_loss	1.0000
15:78163712:GTA:G	acceptor_loss	1.0000
15:78163713:TA:T	acceptor_loss	1.0000
15:78163714:A:AG	acceptor_gain	1.0000
15:78163714:AGAT:A	acceptor_gain	1.0000
15:78163715:G:GA	acceptor_loss	1.0000
15:78163715:G:GG	acceptor_gain	1.0000
15:78163715:GAT:G	acceptor_gain	1.0000
15:78163715:GATG:G	acceptor_gain	1.0000

AlphaMissense

2417 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:78161728:G:C	R146P	1.000
15:78161748:T:C	Y153H	1.000
15:78162340:T:A	V195D	1.000
15:78162355:A:T	K200I	1.000
15:78162356:A:C	K200N	1.000
15:78162356:A:T	K200N	1.000
15:78163593:A:T	D233V	1.000
15:78163760:T:A	N253K	1.000
15:78163760:T:G	N253K	1.000
15:78163767:G:A	G256R	1.000
15:78163767:G:C	G256R	1.000
15:78163768:G:A	G256E	1.000
15:78163768:G:T	G256V	1.000
15:78157573:G:A	G39E	0.999
15:78157584:G:C	G43R	0.999
15:78157585:G:A	G43D	0.999
15:78160104:T:A	W63R	0.999
15:78160104:T:C	W63R	0.999
15:78160201:T:C	L95S	0.999
15:78160203:A:G	K96E	0.999
15:78160205:A:C	K96N	0.999
15:78160205:A:T	K96N	0.999
15:78161624:T:A	N111K	0.999
15:78161624:T:G	N111K	0.999
15:78161634:C:A	R115S	0.999
15:78161660:T:A	N123K	0.999
15:78161660:T:G	N123K	0.999
15:78161662:T:A	V124D	0.999
15:78161725:T:A	I145N	0.999
15:78161731:A:T	E147V	0.999

dbSNP variants (sampled 300 via entrez): RS1000028333 (15:78164828 C>G,T), RS1000370566 (15:78158216 G>A), RS1000667107 (15:78157887 T>G), RS1000996110 (15:78157457 C>G,T), RS1001039260 (15:78162639 G>A), RS1001066320 (15:78170837 G>A), RS1001125372 (15:78164393 C>T), RS1001232503 (15:78158906 C>T), RS1001350449 (15:78170454 T>A), RS1001581244 (15:78164255 C>G), RS1001724307 (15:78151551 G>T), RS1001776874 (15:78151816 T>A), RS1001825762 (15:78149188 T>C,G), RS1001940383 (15:78149389 C>A,G,T), RS1001967008 (15:78172023 C>T)

Disease associations

OMIM: gene MIM:601149 | disease phenotypes: MIM:619007, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 90	Strong	Autosomal recessive
retinitis pigmentosa	Strong	Autosomal recessive

Mondo (3): inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa 90 (MONDO:0033563), retinitis pigmentosa (MONDO:0019200)

Orphanet (2): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001133	Constriction of peripheral visual field
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness
HP:0007703	Abnormal retinal pigmentation
HP:0007722	Retinal pigment epithelial atrophy
HP:0007737	Spicular pigmentation of the retina
HP:0007787	Posterior subcapsular cataract
HP:0007843	Attenuation of retinal blood vessels
HP:0007994	Peripheral visual field loss

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003476_6	Eyebrow thickness	1.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296004 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.46	Kd	34.36	nM	CHEMBL5653589
7.46	ED50	34.36	nM	CHEMBL5653589
6.08	Kd	836.3	nM	CHEMBL3752910
6.08	ED50	836.3	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148571: Binding affinity to human IDH3A incubated for 45 mins by Kinobead based pull down assay	kd	0.0344	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148571: Binding affinity to human IDH3A incubated for 45 mins by Kinobead based pull down assay	kd	0.8363	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	7
Rotenone	decreases expression, increases expression	4
Benzo(a)pyrene	increases expression, increases mutagenesis, affects cotreatment, decreases expression	3
bisphenol A	decreases expression, increases expression	2
trichostatin A	affects expression, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Cannabidiol	affects cotreatment, increases expression	2
Copper	affects binding, decreases expression	2
Estradiol	affects binding, increases reaction, increases expression	2
Manganese	affects binding, affects cotreatment, increases abundance, increases expression	2
Ozone	affects cotreatment, decreases expression, affects expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	increases expression	2
bisphenol F	increases expression	1
moringin	affects cotreatment, increases expression	1
2,4,6-tribromophenol	decreases expression	1
bufotalin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
metoprine	decreases expression	1
chlormidazole	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	decreases expression	1
tributyltin	affects reaction, decreases expression	1
2,6-dichloro-4-nitrophenol	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118946	Binding	Binding affinity to IDH3A in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa