MDH2

Summary

MDH2 (malate dehydrogenase 2, HGNC:6971) is a protein-coding gene on chromosome 7q11.23, encoding Malate dehydrogenase, mitochondrial (P40926).

Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4191 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 51 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 747 total — 13 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005918

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6971
Approved symbol	MDH2
Name	malate dehydrogenase 2
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146701
Ensembl biotype	protein_coding
OMIM	154100
Entrez	4191

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000315758, ENST00000424167, ENST00000432020, ENST00000443006, ENST00000461263, ENST00000461665, ENST00000490105, ENST00000492663, ENST00000854578, ENST00000854579, ENST00000854580, ENST00000854581, ENST00000930051, ENST00000930052, ENST00000930053, ENST00000971443

RefSeq mRNA: 3 — MANE Select: NM_005918 NM_001282403, NM_001282404, NM_005918

CCDS: CCDS5581, CCDS64691, CCDS75622

Canonical transcript exons

ENST00000315758 — 9 exons

Exon	Start	End
ENSE00001663150	76066279	76067508
ENSE00001703408	76064802	76064953
ENSE00001803022	76060373	76060498
ENSE00001905498	76048106	76048226
ENSE00003460373	76054830	76054998
ENSE00003487911	76057969	76058078
ENSE00003582996	76063515	76063592
ENSE00003619690	76057410	76057493
ENSE00003629127	76064339	76064438

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 333.0049 / max 1978.5069, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79139	309.2836	1828
79140	22.7835	1798
79142	0.9378	499

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of tongue	UBERON:0011876	99.60	gold quality
heart right ventricle	UBERON:0002080	99.42	gold quality
type B pancreatic cell	CL:0000169	99.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.37	gold quality
pharyngeal mucosa	UBERON:0000355	99.33	gold quality
gastrocnemius	UBERON:0001388	99.33	gold quality
biceps brachii	UBERON:0001507	99.33	gold quality
skeletal muscle tissue	UBERON:0001134	99.31	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.31	gold quality
tongue	UBERON:0001723	99.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.25	gold quality
penis	UBERON:0000989	99.24	gold quality
diaphragm	UBERON:0001103	99.21	gold quality
gluteal muscle	UBERON:0002000	99.19	gold quality
left ventricle myocardium	UBERON:0006566	99.19	gold quality
vastus lateralis	UBERON:0001379	99.18	gold quality
deltoid	UBERON:0001476	99.18	gold quality
apex of heart	UBERON:0002098	99.12	gold quality
cardiac ventricle	UBERON:0002082	99.09	gold quality
triceps brachii	UBERON:0001509	99.07	gold quality
heart left ventricle	UBERON:0002084	99.07	gold quality
muscle tissue	UBERON:0002385	99.06	gold quality
superior surface of tongue	UBERON:0007371	99.03	gold quality
muscle of leg	UBERON:0001383	98.96	gold quality
nipple	UBERON:0002030	98.96	gold quality
cardiac atrium	UBERON:0002081	98.96	gold quality
right atrium auricular region	UBERON:0006631	98.95	gold quality
muscle organ	UBERON:0001630	98.93	gold quality
skeletal muscle organ	UBERON:0014892	98.93	gold quality
myocardium	UBERON:0002349	98.91	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	23.20
E-MTAB-9067	yes	21.37
E-CURD-112	yes	10.22
E-MTAB-9388	yes	7.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting MDH2, 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-4668-3P	100.00	68.74	2635
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-4717-5P	98.19	67.97	894

Literature-anchored findings (GeneRIF, showing 11)

• L-2-hydroxyglutarate accumulates as a result of a deficiency in FAD-linked L-2-hydroxyglutarate dehydrogenase. mitochondrial L-malate dehydrogenase is responsible for the excretion of L-2-hydroxyglutarate in this condition. (PMID:17603759)
• Data indicate that acetyl-CoA acetyltransferase (ACAT1) and malate dehydrogenase (MDH2) are involved in various drug-resistance-forming mechanisms. (PMID:25639359)
• Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene. (PMID:25766404)
• loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children (PMID:27989324)
• these data suggest that MDH2, functioning as an RNA-binding protein, is involved in the posttranscriptional downregulation of SCN1A expression under seizure condition. (PMID:28433711)
• his study suggests that MDH2 pathogenic variants may play a role in pheochromocytoma/paraganglioma (PPGL) susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes (PMID:30008476)
• Urinary malate dehydrogenase 2 is a new biomarker for early detection of non-small-cell lung cancer. (PMID:33565687)
• Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia. (PMID:34718610)
• Bi-allelic variants in MDH2: Expanding the clinical phenotype. (PMID:34766628)
• Structural Comparison of hMDH2 Complexed with Natural Substrates and Cofactors: The Importance of Phosphate Binding for Active Conformation and Catalysis. (PMID:36139014)
• Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis. (PMID:36159820)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	mdh2	ENSDARG00000043371
mus_musculus	Mdh2	ENSMUSG00000019179
rattus_norvegicus	Mdh2	ENSRNOG00000001440
drosophila_melanogaster	CG10748	FBGN0036327
drosophila_melanogaster	CG10749	FBGN0036328
drosophila_melanogaster	Mdh2	FBGN0262559
caenorhabditis_elegans		WBGENE00003162

Paralogs (5): LDHB (ENSG00000111716), LDHA (ENSG00000134333), LDHC (ENSG00000166796), LDHAL6A (ENSG00000166800), LDHAL6B (ENSG00000171989)

Protein

Protein identifiers

Malate dehydrogenase, mitochondrial — P40926 (reviewed: P40926)

All UniProt accessions (4): P40926, A0A024R4K3, G3XAL0, U3KQ63

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Acetylation is enhanced by up to 67% after treatment either with trichostin A (TSA) or with nicotinamide (NAM) with the appearance of tri- and tetraacetylations. Glucose also increases acetylation by about 60%.

Disease relevance. Developmental and epileptic encephalopathy 51 (DEE51) [MIM:617339] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE51 is an autosomal recessive form characterized by onset of intractable seizures and hypotonia in the first days or weeks of life, and severely delayed psychomotor development. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Enzyme activity is enhanced by acetylation.

Similarity. Belongs to the LDH/MDH superfamily. MDH type 1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P40926-1	1	yes
P40926-2	2

RefSeq proteins (3): NP_001269332, NP_001269333, NP_005909* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001236	Lactate/malate_DH_N	Domain
IPR001252	Malate_DH_AS	Active_site
IPR001557	L-lactate/malate_DH	Family
IPR010097	Malate_DH_type1	Family
IPR015955	Lactate_DH/Glyco_Ohase_4_C	Homologous_superfamily
IPR022383	Lactate/malate_DH_C	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00056, PF02866

Enzyme classification (BRENDA):

• EC 1.1.1.37 — (S)-malate dehydrogenase (NAD+, oxaloacetate-forming) (BRENDA: 181 organisms, 139 substrates, 209 inhibitors, 501 Km, 92 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
OXALOACETATE	0.0001–29.5	152
NADH	0.0014–1.4	132
NAD+	0.0009–129	85
(S)-MALATE	0.0001–15	47
L-MALATE	0.014–98.4	42
MALATE	0.55–3.53	4
NADPH	0.0426–0.25	4
3-ACETYLPYRIDINE-ADENINE DINUCLEOTIDE	0.0495–0.1114	3
PYRUVATE	2.2–2.9	3
3,5-DIIODO-4-HYDROXYPHENYLPYRUVATE	0.04–0.043	2
PHENYLPYRUVATE	1.6–4.8	2
3-ACETYLNICOTINAMIDE-NAD+	0.089	1
3-ACETYLPYRIDINE ADENINE DINUCLEOTIDE	0.0667	1
4-HYDROXYPHENYLPYRUVATE	1.9	1
ACETYLPYRIDINE ADENINE DINUCLEOTIDE	0.022	1

Catalyzed reactions (Rhea), 1 shown:

• (S)-malate + NAD(+) = oxaloacetate + NADH + H(+) (RHEA:21432)

UniProt features (83 total): modified residue 33, helix 13, strand 12, binding site 9, sequence variant 4, mutagenesis site 4, turn 2, transit peptide 1, chain 1, active site 1, glycosylation site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2DFD	X-RAY DIFFRACTION	1.9
4WLE	X-RAY DIFFRACTION	1.9
4WLU	X-RAY DIFFRACTION	2.14
4WLF	X-RAY DIFFRACTION	2.2
4WLN	X-RAY DIFFRACTION	2.28
4WLV	X-RAY DIFFRACTION	2.4
4WLO	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40926-F1	93.49	0.87

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 (1): 200 (proton acceptor)

Ligand- & substrate-binding residues (9): 176; 251; 31–37; 57; 104; 110; 117; 140–142; 142

Post-translational modifications (33): 78, 78, 91, 91, 165, 185, 185, 203, 215, 215, 239, 239, 239, 246, 269, 296, 296, 301, 301, 307 …

Glycosylation sites (1): 33

Mutagenesis-validated functional residues (4):

Position	Phenotype
185	no activation of enzyme activity on treatment with tsa or nam; when associated with r-301; r-307 and r-314.
301	no activation of enzyme activity on treatment with tsa or nam; when associated with r-185; r-307 and r-314.
307	no activation of enzyme activity on treatment with tsa or nam; when associated with r-185; r-301 and r-314.
314	no activation of enzyme activity on treatment with tsa or nam; when associated with r-185; r-301 and r-307.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9856872	Malate-aspartate shuttle
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-611105	Respiratory electron transport

MSigDB gene sets: 392 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NADPLUS_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_MONOSACCHARIDE_BIOSYNTHETIC_PROCESS, MOOTHA_GLUCONEOGENESIS, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_GLUCOSE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (7): gluconeogenesis (GO:0006094), tricarboxylic acid cycle (GO:0006099), malate metabolic process (GO:0006108), aerobic respiration (GO:0009060), malate-aspartate shuttle (GO:0043490), obsolete NADH metabolic process (GO:0006734), carboxylic acid metabolic process (GO:0019752)

GO Molecular Function (8): RNA binding (GO:0003723), L-malate dehydrogenase (NAD+) activity (GO:0030060), identical protein binding (GO:0042802), L-malate dehydrogenase (NADP+) activity (GO:0046554), catalytic activity (GO:0003824), oxidoreductase activity (GO:0016491), malate dehydrogenase activity (GO:0016615), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	2
Metabolism of proteins	1
Respiratory electron transport	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
malate dehydrogenase activity	2
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	2
oxidoreductase activity, acting on CH-OH group of donors	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
glucose metabolic process	1
hexose biosynthetic process	1
aerobic respiration	1
primary metabolic process	1
dicarboxylic acid metabolic process	1
cellular respiration	1
L-aspartate:2-oxoglutarate transaminase activity	1
NAD+ metabolic process	1
L-malate dehydrogenase (NAD+) activity	1
mitochondrial transmembrane transport	1
oxoacid metabolic process	1
nucleic acid binding	1
protein binding	1
molecular_function	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
extracellular vesicle	1

Protein interactions and networks

STRING

4997 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MDH2	IDH2	P48735	972
MDH2	IDH1	O75874	933
MDH2	ACO2	Q99798	908
MDH2	GOT2	P00505	902
MDH2	ACO1	P21399	867
MDH2	STX2	P32856	856
MDH2	CS	O75390	854
MDH2	FH	P07954	810
MDH2	GNPTAB	Q3T906	797
MDH2	OGDH	Q02218	792
MDH2	SDHA	P31040	774
MDH2	SLC25A11	Q02978	771
MDH2	PURA	Q00577	768
MDH2	PDHA1	P08559	761
MDH2	SDHB	P21912	757

IntAct

116 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
rep	ACTN4	psi-mi:“MI:0914”(association)	0.480
MDH2	rep	psi-mi:“MI:0915”(physical association)	0.480
steC	SCD	psi-mi:“MI:0914”(association)	0.460
MDH2	ATP5F1A	psi-mi:“MI:0915”(physical association)	0.400
MDH2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
G2E3	MDH2	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
MDH2	PCNA	psi-mi:“MI:0915”(physical association)	0.400
MDH2	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
PHOSPHO1	DDX39A	psi-mi:“MI:0914”(association)	0.350
PPP1CA	ACO2	psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
COQ2	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
DLST		psi-mi:“MI:0914”(association)	0.350
DNM1L		psi-mi:“MI:0914”(association)	0.350
HSD17B10	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
PARK7	SAP18	psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350
SOAT1	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
SOD1	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (636): MDH2 (Affinity Capture-MS), MDH2 (Affinity Capture-MS), MDH2 (Affinity Capture-MS), MDH2 (Affinity Capture-MS), MDH2 (Affinity Capture-MS), CORO1C (Co-fractionation), IDH3A (Co-fractionation), MDH2 (Co-fractionation), MDH2 (Co-fractionation), MDH2 (Co-fractionation), MDH2 (Co-fractionation), MDH2 (Co-fractionation), MDH2 (Co-fractionation), MDH2 (Co-fractionation), MDH2 (Co-fractionation)

ESM2 similar proteins: A1AGC9, A7ZSD0, A8A545, A8AQC8, A8G8Y7, A9MNX5, B1IQP3, B1LGK2, B1XHK9, B2U1U9, B5YSW2, B6I1V4, B7LHU4, B7LRL0, B7M0U8, B7MBZ7, B7N0M1, B7NDL4, B7NKU9, B7UJW8, C4ZSX4, K0J107, O02640, P00346, P04636, P08249, P17505, P17783, P40926, P46487, P61889, P61890, P61891, P83373, Q0T052, Q0TCN0, Q1R6A3, Q31WA4, Q32BA3, Q32LG3

Diamond homologs: A1AGC9, A1JIV0, A4TRK3, A4WF48, A6TEQ3, A7FMU2, A7MNR3, A7ZSD0, A8A545, A8AQC8, A8G8Y7, A9MNX5, A9N855, A9R584, B0UUR6, B1IQP3, B1JMK1, B1LGK2, B1XHK9, B2K2N5, B2U1U9, B2VGW7, B4F2A1, B4T769, B4TJT3, B4TWK9, B5BGR3, B5F7L9, B5FGF5, B5FIT7, B5R0N2, B5REV7, B5XSQ7, B5YSW2, B6EL39, B6I1V4, B7LHU4, B7LRL0, B7M0U8, B7MBZ7

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
MDH2	“down-regulates quantity”	(S)-malate(2-)	“chemical modification”
MDH2	“up-regulates quantity”	oxaloacetate(2-)	“chemical modification”
MDH2	“up-regulates quantity”	NADH	“chemical modification”
MDH2	“down-regulates quantity”	NAD(1-)	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 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
Signaling by Interleukins	9	5.8×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	5	13.9×	6e-03
positive regulation of miRNA transcription	6	13.8×	2e-03
mitophagy	5	12.6×	8e-03
response to ethanol	8	9.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	7
Uncertain significance	396
Likely benign	272
Benign	22

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1497026	NM_005918.4(MDH2):c.591del (p.Ile197fs)	Pathogenic
1505082	NM_005918.4(MDH2):c.429+1G>T	Pathogenic
1523821	NM_005918.4(MDH2):c.167_168del (p.Leu55_Tyr56insTer)	Pathogenic
2231968	NM_005918.4(MDH2):c.566del (p.Pro189fs)	Pathogenic
265770	NM_005918.4(MDH2):c.620C>T (p.Pro207Leu)	Pathogenic
266121	NM_005918.4(MDH2):c.596del (p.Gly199fs)	Pathogenic
267277	NM_005918.4(MDH2):c.109G>A (p.Gly37Arg)	Pathogenic
2864443	NM_005918.4(MDH2):c.543del (p.Ala182fs)	Pathogenic
2871161	NM_005918.4(MDH2):c.489del (p.Asn164fs)	Pathogenic
3384890	NC_000007.13:g.(75687397_75689690)(75696827?)del	Pathogenic
3661531	NM_005918.4(MDH2):c.205dup (p.Ser69fs)	Pathogenic
4779207	NM_005918.4(MDH2):c.291del (p.Ile98fs)	Pathogenic
4805815	NM_005918.4(MDH2):c.571C>T (p.Arg191Ter)	Pathogenic
1411713	NM_005918.4(MDH2):c.733+2T>C	Likely pathogenic
1428487	NM_005918.4(MDH2):c.236-2A>C	Likely pathogenic
1804008	NM_005918.4(MDH2):c.884G>T (p.Gly295Val)	Likely pathogenic
2230990	NM_005918.4(MDH2):c.556-1G>C	Likely pathogenic
3619506	NM_005918.4(MDH2):c.633+1G>A	Likely pathogenic
3622166	NM_005918.4(MDH2):c.320-1G>A	Likely pathogenic
3653755	NM_005918.4(MDH2):c.734-1G>C	Likely pathogenic

SpliceAI

1299 predictions. Top by Δscore:

Variant	Effect	Δscore
7:76054994:GAAAG:G	donor_loss	1.0000
7:76054996:AAGG:A	donor_loss	1.0000
7:76054997:AG:A	donor_loss	1.0000
7:76054998:GG:G	donor_loss	1.0000
7:76054999:G:A	donor_loss	1.0000
7:76055000:T:G	donor_loss	1.0000
7:76057961:A:AG	acceptor_gain	1.0000
7:76057963:TTCCA:T	acceptor_loss	1.0000
7:76057964:TCCAG:T	acceptor_loss	1.0000
7:76057965:CCAGG:C	acceptor_loss	1.0000
7:76057966:CAGGC:C	acceptor_loss	1.0000
7:76057967:A:AG	acceptor_gain	1.0000
7:76057967:AG:A	acceptor_gain	1.0000
7:76057967:AGGC:A	acceptor_loss	1.0000
7:76057968:G:A	acceptor_loss	1.0000
7:76057968:G:GA	acceptor_gain	1.0000
7:76057968:GG:G	acceptor_gain	1.0000
7:76057968:GGC:G	acceptor_gain	1.0000
7:76057968:GGCA:G	acceptor_gain	1.0000
7:76057968:GGCAT:G	acceptor_gain	1.0000
7:76058074:ATCCG:A	donor_gain	1.0000
7:76058075:TCCG:T	donor_gain	1.0000
7:76058077:CGGTG:C	donor_loss	1.0000
7:76058079:G:GG	donor_gain	1.0000
7:76058080:T:G	donor_loss	1.0000
7:76060396:A:AG	acceptor_gain	1.0000
7:76060397:G:GG	acceptor_gain	1.0000
7:76060397:GCA:G	acceptor_gain	1.0000
7:76060496:AAGG:A	donor_loss	1.0000
7:76060497:AGGT:A	donor_loss	1.0000

AlphaMissense

2180 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:76054855:G:A	G31E	1.000
7:76054864:G:A	G34E	1.000
7:76054873:G:A	G37E	1.000
7:76057476:G:A	G101E	1.000
7:76057987:T:C	L113P	1.000
7:76058075:T:A	N142K	1.000
7:76058075:T:G	N142K	1.000
7:76060378:T:A	N145K	1.000
7:76060378:T:G	N145K	1.000
7:76060461:A:T	D173V	1.000
7:76054854:G:A	G31R	0.999
7:76054854:G:C	G31R	0.999
7:76054854:G:T	G31W	0.999
7:76054872:G:A	G37R	0.999
7:76054872:G:C	G37R	0.999
7:76054872:G:T	G37W	0.999
7:76054873:G:T	G37V	0.999
7:76054888:T:C	L42P	0.999
7:76054932:G:C	D57H	0.999
7:76054933:A:C	D57A	0.999
7:76054933:A:T	D57V	0.999
7:76054950:G:A	G63R	0.999
7:76054950:G:C	G63R	0.999
7:76054951:G:A	G63E	0.999
7:76054962:G:C	D67H	0.999
7:76054962:G:T	D67Y	0.999
7:76054963:A:C	D67A	0.999
7:76054963:A:T	D67V	0.999
7:76054966:T:C	L68P	0.999
7:76057461:T:A	V96E	0.999

dbSNP variants (sampled 300 via entrez): RS1000078138 (7:76058933 C>A), RS1000139865 (7:76050022 G>A), RS1000405232 (7:76061327 G>A), RS1000478881 (7:76064946 T>C), RS1000508623 (7:76065223 C>G,T), RS1000664417 (7:76059951 G>A), RS1000734070 (7:76061083 C>G,T), RS1001329840 (7:76062450 C>T), RS1001404866 (7:76062611 C>T), RS1001661820 (7:76047611 T>C), RS1001985163 (7:76047353 T>C), RS1002180621 (7:76057293 A>C,G), RS1002409949 (7:76051140 C>T), RS1002591261 (7:76048300 A>G,T), RS1003074275 (7:76053867 G>C)

Disease associations

OMIM: gene MIM:154100 | disease phenotypes: MIM:617339, MIM:168000, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 51	Strong	Autosomal recessive
hereditary pheochromocytoma-paraganglioma	Supportive	Autosomal dominant

Mondo (3): developmental and epileptic encephalopathy, 51 (MONDO:0015025), hereditary pheochromocytoma-paraganglioma (MONDO:0017366), developmental and epileptic encephalopathy, 1 (MONDO:0010632)

Orphanet (1): Hereditary pheochromocytoma-paraganglioma (Orphanet:29072)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000405	Conductive hearing impairment
HP:0000486	Strabismus
HP:0000510	Rod-cone dystrophy
HP:0000526	Aniridia
HP:0000740	Episodic paroxysmal anxiety
HP:0000790	Hematuria
HP:0000817	Reduced eye contact
HP:0000980	Pallor
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001293	Cranial nerve compression
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001342	Cerebral hemorrhage
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001605	Vocal cord paralysis
HP:0001618	Dysphonia
HP:0001635	Congestive heart failure
HP:0001824	Weight loss
HP:0001962	Palpitations

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009801_16	Coffee consumption	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006781	coffee consumption measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5917 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 81,643 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1624	LEVOTHYROXINE	4	81,643

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

Binding affinities (BindingDB)

2 measured of 3 human assays (3 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4098767	IC50	1360 nM
CHEMBL4069043	IC50	26900 nM

ChEMBL bioactivities

42 potent at pChembl≥5 of 54 total, top 41 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	Kd	19.78	nM	CHEMBL3752910
7.70	ED50	19.78	nM	CHEMBL3752910
7.27	Kd	53.32	nM	CHEMBL5653589
7.27	ED50	53.32	nM	CHEMBL5653589
6.11	IC50	770	nM	CHEMBL577395
6.02	Ki	950	nM	CHEMBL4068781
5.97	IC50	1060	nM	CHEMBL4068781
5.96	IC50	1110	nM	CHEMBL4080721
5.96	IC50	1110	nM	CHEMBL4091027
5.96	IC50	1100	nM	CHEMBL577566
5.88	IC50	1320	nM	CHEMBL4074947
5.87	IC50	1360	nM	CHEMBL4098767
5.82	IC50	1530	nM	CHEMBL4073085
5.80	IC50	1600	nM	CHEMBL586055
5.80	IC50	1600	nM	CHEMBL575106
5.77	IC50	1690	nM	CHEMBL4087903
5.75	IC50	1800	nM	CHEMBL568703
5.72	Ki	1900	nM	CHEMBL427092
5.72	IC50	1890	nM	CHEMBL4065526
5.62	IC50	2400	nM	PAULLONE
5.57	IC50	2700	nM	CHEMBL578640
5.57	IC50	2700	nM	CHEMBL574898
5.54	IC50	2900	nM	CHEMBL4099949
5.38	IC50	4200	nM	CHEMBL574918
5.37	Ki	4300	nM	CHEMBL3359147
5.37	IC50	4300	nM	CHEMBL575107
5.36	IC50	4400	nM	CHEMBL583199
5.34	IC50	4600	nM	CHEMBL4074694
5.32	IC50	4786	nM	CHEMBL157654
5.30	IC50	5000	nM	CHEMBL157654
5.27	IC50	5400	nM	CHEMBL4086789
5.26	IC50	5500	nM	CHEMBL3359147
5.23	IC50	5880	nM	CHEMBL4096306
5.21	IC50	6200	nM	CHEMBL573145
5.21	IC50	6200	nM	CHEMBL574919
5.20	IC50	6300	nM	CHEMBL427092
5.15	IC50	7100	nM	CHEMBL3359141
5.10	IC50	7900	nM	CHEMBL575951
5.07	IC50	8480	nM	CHEMBL242020
5.05	IC50	8920	nM	CHEMBL4105436
5.00	IC50	9900	nM	CHEMBL565663

PubChem BioAssay actives

40 with measured affinity, of 183 total; 35 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148738: Binding affinity to human MDH2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0198	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148738: Binding affinity to human MDH2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0533	uM
9-tert-butyl-5-[(3,4-dichlorophenyl)methyl]-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	0.7700	uM
methyl 3-[3-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]propanoylamino]benzoate	1476505: Competitive inhibition of human MDH2 using oxaloacetic acid as substrate in presence of NADH after 30 mins by double reciprocal plot analysis	ki	0.9500	uM
9-bromo-5-[(3,4-dichlorophenyl)methyl]-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	1.1000	uM
methyl 3-[4-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]butanoylamino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.1100	uM
methyl 4-hydroxy-3-[4-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]butanoylamino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.1100	uM
methyl 3-[[2-methyl-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]propanoyl]amino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.3200	uM
methyl 3-[[2-[4-(1-adamantyl)phenoxy]-2-methylpropanoyl]amino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.3600	uM
N-[4-(trifluoromethyl)phenyl]-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetamide	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.5300	uM
5-benzyl-9-tert-butyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	1.6000	uM
9-bromo-5-[(4-methylphenyl)methyl]-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	1.6000	uM
methyl 4-prop-2-ynoxy-3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.6900	uM
9-bromo-5-[(4-methoxyphenyl)methyl]-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	1.8000	uM
methyl 4-hydroxy-3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.8900	uM
methyl 3-[[2-[4-(1-adamantyl)phenoxy]acetyl]amino]-4-hydroxybenzoate	1170138: Competitive inhibition of MDH2 (unknown origin) using varying NADH level by oxaloacetate-dependent NADH oxidation based Lineweaver-Burk plot	ki	1.9000	uM
5-benzyl-9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	2.4000	uM
5-benzyl-9-chloro-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	2.7000	uM
octyl 6-oxo-7,12-dihydro-5H-indolo[3,2-d][1]benzazepine-9-carboxylate	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	2.7000	uM
N-[4-(4-methylpiperazin-1-yl)phenyl]-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetamide	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	2.9000	uM
5-benzyl-9-(trifluoromethyl)-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	4.2000	uM
hexyl 6-oxo-7,12-dihydro-5H-indolo[3,2-d][1]benzazepine-9-carboxylate	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	4.3000	uM
prop-2-ynyl 3-[[2-[4-(1-adamantyl)-2-[3-(trifluoromethyl)diazirin-3-yl]phenoxy]acetyl]amino]-4-hydroxybenzoate	1170138: Competitive inhibition of MDH2 (unknown origin) using varying NADH level by oxaloacetate-dependent NADH oxidation based Lineweaver-Burk plot	ki	4.3000	uM
pentyl 6-oxo-7,12-dihydro-5H-indolo[3,2-d][1]benzazepine-9-carboxylate	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	4.4000	uM
methyl 4-hydroxy-3-[3-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]propanoylamino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	4.6000	uM
7-[(3,4-dichlorophenyl)methoxy]-4-oxo-1H-quinoline-3-carboxylic acid	1149734: Inhibition of malate dehydrogenase (unknown origin) by spectrophotometry	ic50	4.7863	uM
1-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanone	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	5.4000	uM
prop-2-ynyl 4-hydroxy-3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	5.8800	uM
5-benzyl-9-methyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	6.2000	uM
propyl 6-oxo-7,12-dihydro-5H-indolo[3,2-d][1]benzazepine-9-carboxylate	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	6.2000	uM
prop-2-ynyl 3-[[2-[4-(1-adamantyl)phenoxy]acetyl]amino]-4-hydroxybenzoate	1170132: Inhibition of MDH2 (unknown origin) pre-incubated for 1 hr followed by malate and NAD+ addition	ic50	7.1000	uM
5-[(3,4-dichlorophenyl)methyl]-7,12-dihydroindolo[3,2-d][1]benzazepin-6-one	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	7.9000	uM
2-[4-[2-[5-hydroxy-2-[(4-methoxyphenyl)methylcarbamoyl]-4-oxochromen-7-yl]oxyethyl]-2-methoxyanilino]-2-oxoacetic acid	747625: Inhibition of human recombinant carboxy-terminal his-tagged MDH-2 (20 to 338) expressed in Escherichia coli using oxaloacetic acid as substrate after 10 mins by UV endpoint analysis	ic50	8.4800	uM
methyl 3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476477: Inhibition of human MDH2 after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	8.9200	uM
butyl 6-oxo-7,12-dihydro-5H-indolo[3,2-d][1]benzazepine-9-carboxylate	442253: Inhibition of mitochondrial malate dehydrogenase by spectrophotometry	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases expression, decreases expression	4
bisphenol A	decreases expression, increases expression	3
Doxorubicin	increases expression, decreases response to substance	2
Valproic Acid	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
bismuth tripotassium dicitrate	increases expression	1
lasiocarpine	decreases expression	1
uranyl acetate	affects expression	1
lead acetate	affects cotreatment, increases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, increases reaction	1
nickel chloride	increases activity	1
epigallocatechin gallate	decreases expression	1
celastrol	decreases expression	1
dinophysistoxin 1	decreases expression	1
azoxystrobin	increases expression	1
chloropicrin	increases expression	1
gedunin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
bromovanin	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

28 unique, capped per target: 28 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1040546	Binding	Inhibition of mitochondrial malate dehydrogenase assessed as residual enzyme activity at 10 uM by spectrophotometry	Development of 5-benzylpaullones and paullone-9-carboxylic acid alkyl esters as selective inhibitors of mitochondrial malate dehydrogenase (mMDH). — Eur J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3AX	Abcam HEK293T MDH2 KO	Transformed cell line	Female
CVCL_B5KB	HAP1 MDH2 (-) 2	Cancer cell line	Male
CVCL_XQ36	HAP1 MDH2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition