MDH1

Summary

MDH1 (malate dehydrogenase 1, HGNC:6970) is a protein-coding gene on chromosome 2p15, encoding Malate dehydrogenase, cytoplasmic (P40925). Catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH.

This gene encodes an enzyme that catalyzes the NAD/NADH-dependent, reversible oxidation of malate to oxaloacetate in many metabolic pathways, including the citric acid cycle. Two main isozymes are known to exist in eukaryotic cells: one is found in the mitochondrial matrix and the other in the cytoplasm. This gene encodes the cytosolic isozyme, which plays a key role in the malate-aspartate shuttle that allows malate to pass through the mitochondrial membrane to be transformed into oxaloacetate for further cellular processes. Alternatively spliced transcript variants have been found for this gene. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Pseudogenes have been identified on chromosomes X and 6.

Source: NCBI Gene 4190 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 88 (Moderate, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 56 total — 1 pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005917

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6970
Approved symbol	MDH1
Name	malate dehydrogenase 1
Location	2p15
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000014641
Ensembl biotype	protein_coding
OMIM	154200
Entrez	4190

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 35 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000233114, ENST00000409476, ENST00000409908, ENST00000421012, ENST00000432309, ENST00000436321, ENST00000442225, ENST00000454035, ENST00000462944, ENST00000472098, ENST00000484538, ENST00000485155, ENST00000485781, ENST00000495083, ENST00000539945, ENST00000544381, ENST00000906783, ENST00000906784, ENST00000906785, ENST00000906786, ENST00000906787, ENST00000906788, ENST00000906789, ENST00000906790, ENST00000906791, ENST00000906792, ENST00000920243, ENST00000920244, ENST00000920245, ENST00000920246, ENST00000920247, ENST00000920248, ENST00000920249, ENST00000920250, ENST00000920251, ENST00000920252, ENST00000920253, ENST00000920254, ENST00000920255, ENST00000967562, ENST00000967563, ENST00000967564

RefSeq mRNA: 4 — MANE Select: NM_005917 NM_001199111, NM_001199112, NM_001316374, NM_005917

CCDS: CCDS1874, CCDS56121, CCDS92766

Canonical transcript exons

ENST00000233114 — 9 exons

Exon	Start	End
ENSE00000758082	63604696	63604872
ENSE00000758084	63605280	63605393
ENSE00000758086	63605939	63606028
ENSE00001897159	63606862	63607197
ENSE00003559734	63588963	63589046
ENSE00003573337	63594488	63594586
ENSE00003625348	63597399	63597574
ENSE00003671293	63599170	63599292
ENSE00003785495	63595423	63595519

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 147.7878 / max 1089.8363, expressed in 1827 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20534	128.0611	1827
20535	13.5697	1719
202209	5.5742	1663
20537	0.3932	175
20536	0.1896	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.87	gold quality
heart right ventricle	UBERON:0002080	99.86	gold quality
pons	UBERON:0000988	99.83	gold quality
middle temporal gyrus	UBERON:0002771	99.82	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.76	gold quality
orbitofrontal cortex	UBERON:0004167	99.74	gold quality
cardiac ventricle	UBERON:0002082	99.69	gold quality
heart left ventricle	UBERON:0002084	99.69	gold quality
apex of heart	UBERON:0002098	99.67	gold quality
prefrontal cortex	UBERON:0000451	99.66	gold quality
right atrium auricular region	UBERON:0006631	99.65	gold quality
frontal pole	UBERON:0002795	99.63	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.63	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.61	gold quality
vena cava	UBERON:0004087	99.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.56	gold quality
postcentral gyrus	UBERON:0002581	99.55	gold quality
right frontal lobe	UBERON:0002810	99.55	gold quality
body of tongue	UBERON:0011876	99.55	gold quality
parietal lobe	UBERON:0001872	99.53	gold quality
frontal cortex	UBERON:0001870	99.52	gold quality
superior vestibular nucleus	UBERON:0007227	99.52	gold quality
diaphragm	UBERON:0001103	99.50	gold quality
substantia nigra pars compacta	UBERON:0001965	99.50	gold quality
neocortex	UBERON:0001950	99.43	gold quality
endothelial cell	CL:0000115	99.41	gold quality
biceps brachii	UBERON:0001507	99.41	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.41	gold quality
cardiac atrium	UBERON:0002081	99.40	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	31.63
E-HCAD-25	yes	9.38
E-GEOD-84465	yes	6.73
E-HCAD-5	no	1007.92
E-MTAB-8559	no	494.76
E-MTAB-7052	no	378.91
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

18 targeting MDH1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-649	97.96	67.21	704
HSA-MIR-215-3P	97.02	68.01	1209
HSA-MIR-125B-2-3P	96.69	68.38	1210

Literature-anchored findings (GeneRIF, showing 12)

• expression of MDH1 is maintained in the adult heart but is not present in levels as high as in the fetus (PMID:15565635)
• This protein has been found differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19110265)
• Malate Dehydrogenase directly regulates the Tumor Suppressor Protein p53-dependent apoptosis upon glucose deprivation and involved in maintaining cellular metabolic state and further determining cell death. (PMID:19229245)
• The MDH1 gene is not the cause of RP28-linked autosomal recessive retinitis pigmentosa. (PMID:20011630)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• adipogenic differentiation may be regulated by the acetylation of MDH1 (PMID:22693256)
• Arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer. (PMID:27840030)
• Data show that in the endogenous readthrough of the human MDH1 stop codon, the stop codon can encode tryptophan and arginine, and is tissue-specific. (PMID:27881739)
• Proliferating cells rely on both MDH1 and LDH to replenish cytosolic NAD. (PMID:28263970)
• expression of miR-126-5p suppresses the enzymatic activity of MDH1, mitochondrial respiration and caused cell death in non-small cell lung carcinoma cell lines. (PMID:29574159)
• MDH1 deficiency is a new metabolic defect in the malate-aspartate shuttle and is associated with a severe neurodevelopmental phenotype. (PMID:31538237)
• Evaluation of Human Cerebrospinal Fluid Malate Dehydrogenase 1 as a Marker in Genetic Prion Disease Patients. (PMID:31795176)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	mdh1aa	ENSDARG00000017772
danio_rerio	mdh1ab	ENSDARG00000103849
mus_musculus	Mdh1	ENSMUSG00000020321
rattus_norvegicus	Mdh1	ENSRNOG00000008103
drosophila_melanogaster	Mdh1	FBGN0262782
caenorhabditis_elegans		WBGENE00018491

Paralogs (1): MDH1B (ENSG00000138400)

Protein

Protein identifiers

Malate dehydrogenase, cytoplasmic — P40925 (reviewed: P40925)

Alternative names: Aromatic alpha-keto acid reductase, Cytosolic malate dehydrogenase

All UniProt accessions (10): P40925, A0A5K1VW95, B8ZZ51, B9A041, C9IZI0, C9JF79, C9JLV6, C9JRL4, F8WFC2, V9HWF2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH. Plays essential roles in the malate-aspartate shuttle and the tricarboxylic acid cycle, important in mitochondrial NADH supply for oxidative phosphorylation. Catalyzes the reduction of 2-oxoglutarate to 2-hydroxyglutarate, leading to elevated reactive oxygen species (ROS).

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol.

Post-translational modifications. ISGylated. Acetylation at Lys-118 dramatically enhances enzymatic activity and promotes adipogenic differentiation.

Disease relevance. Developmental and epileptic encephalopathy 88 (DEE88) [MIM:618959] A form of epileptic encephalopathy, a heterogeneous group of 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. DEE88 is an autosomal recessive severe form characterized by global developmental delay, epilepsy, and progressive microcephaly. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the LDH/MDH superfamily. MDH type 2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P40925-1	1	yes
P40925-2	2
P40925-3	3

RefSeq proteins (4): NP_001186040, NP_001186041, NP_001303303, NP_005908* (*=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
IPR010945	Malate_DH_type2	Family
IPR011274	Malate_DH_NAD-dep_euk	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), 3 shown:

• (2R)-2-hydroxy-3-(4-hydroxyphenyl)propanoate + NAD(+) = 3-(4-hydroxyphenyl)pyruvate + NADH + H(+) (RHEA:10780)
• (S)-malate + NAD(+) = oxaloacetate + NADH + H(+) (RHEA:21432)
• (S)-2-hydroxyglutarate + NAD(+) = 2-oxoglutarate + NADH + H(+) (RHEA:57172)

UniProt features (62 total): strand 15, helix 15, modified residue 14, binding site 9, splice variant 2, turn 2, initiator methionine 1, chain 1, active site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7RM9	X-RAY DIFFRACTION	1.65
7RRL	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40925-F1	96.79	0.93

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): 187 (proton acceptor)

Ligand- & substrate-binding residues (9): 131; 162; 11–17; 42; 92; 98; 105; 112; 129–131

Post-translational modifications (14): 2, 110, 118, 121, 214, 217, 230, 241, 298, 298, 309, 318, 332, 333

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9856872	Malate-aspartate shuttle
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-611105	Respiratory electron transport

MSigDB gene sets: 386 (showing top): MODULE_93, MODY_HIPPOCAMPUS_POSTNATAL, MORF_MBD4, GOBP_NADPPLUS_METABOLIC_PROCESS, MODULE_151, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORF_HDAC1, MORF_RAD21, HSIAO_HOUSEKEEPING_GENES, AACYNNNNTTCCS_UNKNOWN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, MORF_HDAC2, GOBP_OXALOACETATE_METABOLIC_PROCESS, GOBP_NADPLUS_METABOLIC_PROCESS

GO Biological Process (8): tricarboxylic acid cycle (GO:0006099), oxaloacetate metabolic process (GO:0006107), malate metabolic process (GO:0006108), NADP+ metabolic process (GO:0006739), NAD+ metabolic process (GO:0019674), malate-aspartate shuttle (GO:0043490), obsolete NADH metabolic process (GO:0006734), carboxylic acid metabolic process (GO:0019752)

GO Molecular Function (9): malic enzyme activity (GO:0004470), L-malate dehydrogenase (NAD+) activity (GO:0030060), diiodophenylpyruvate reductase (NAD+) activity (GO:0047860), (2R)-hydroxyphenylpyruvate reductase [NAD(P)H] activity (GO:0047995), catalytic activity (GO:0003824), protein binding (GO:0005515), 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 (5): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Respiratory electron transport	1
Metabolism	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
dicarboxylic acid metabolic process	2
purine nucleotide metabolic process	2
nicotinamide nucleotide metabolic process	2
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
cellular anatomical structure	2
aerobic respiration	1
primary metabolic process	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
(2R)-2-hydroxyacid dehydrogenase (NAD+) activity	1
molecular_function	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

75 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ME1	PC	psi-mi:“MI:0403”(colocalization)	0.670
ME1	PC	psi-mi:“MI:0914”(association)	0.670
MDH1	ME1	psi-mi:“MI:2364”(proximity)	0.620
ERBB2	MDH1	psi-mi:“MI:0915”(physical association)	0.550
EGFR	MDH1	psi-mi:“MI:0915”(physical association)	0.550
TERF1	MDH1	psi-mi:“MI:0915”(physical association)	0.510
PC	MDH1	psi-mi:“MI:0914”(association)	0.460
MDH1	PC	psi-mi:“MI:0914”(association)	0.460
MDH1	MDH1	psi-mi:“MI:0407”(direct interaction)	0.440
CSMD2	MDH1	psi-mi:“MI:0915”(physical association)	0.400
MDH1	NFKBIA	psi-mi:“MI:0915”(physical association)	0.400
MDH1	TERF2IP	psi-mi:“MI:0915”(physical association)	0.370
MDH1	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370
MDH1	CHRM2	psi-mi:“MI:0915”(physical association)	0.370
FUS	MDH1	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350

BioGRID (197): ESD (Co-fractionation), GLRX (Co-fractionation), GOT1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), MDH1 (Co-fractionation), PDXK (Co-fractionation), PGM1 (Co-fractionation), PGM2 (Co-fractionation)

ESM2 similar proteins: A0A2Z4HPZ5, A0A7T8F1M6, A4FUZ6, A4G5Z9, A6SY47, B8NU00, C8YTM5, D5JWB3, O13437, O13907, O80934, O88989, P11708, P14152, P16638, P22944, P33677, P36858, P40925, P51106, P51659, P51660, P53396, P54898, P74429, P97852, Q03134, Q07103, Q12068, Q27128, Q2TCH3, Q2TPA8, Q32PF2, Q3T145, Q43772, Q59987, Q5RA68, Q66KC4, Q6P5L8, Q6PAY8

Diamond homologs: A0L5T9, A0PVV1, A0QCI6, A1K5Q9, A1KI28, A1R2B5, A1SMP3, A1T9L9, A1W9K7, A1WV94, A3M928, A4FFX3, A5G320, A5IEF4, A5U1T8, A5WGM2, A9IIS3, A9KFT9, A9NDV1, B0SF41, B0SN74, B0V6R7, B0VQX5, B1W3N4, B2GKC8, B2HRH5, B2HZ52, B2JQD2, B2UKY5, B3PHI3, B6IZN7, B6J7Q0, B7GW58, B7I9D2, C1AMN4, C1B155, C1CY73, C1DB66, C5BU70, O48902

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MDH1	“down-regulates quantity”	(S)-malate(2-)	“chemical modification”
MDH1	“up-regulates quantity”	oxaloacetate(2-)	“chemical modification”
MDH1	“up-regulates quantity”	NADH	“chemical modification”
CARM1	“down-regulates activity”	MDH1	acetylation
MDH1	“down-regulates quantity”	NAD(1-)	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Apoptosis	5	13.5×	3e-03
Cellular Senescence	6	13.3×	9e-04
ESR-mediated signaling	6	12.4×	1e-03
Programmed Cell Death	5	11.8×	5e-03
Signaling by Interleukins	8	8.3×	9e-04
Cellular responses to stress	11	6.5×	2e-04
Diseases of signal transduction by growth factor receptors and second messengers	7	6.4×	6e-03
Cellular responses to stimuli	12	6.1×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	6	24.2×	2e-04
positive regulation of transcription initiation by RNA polymerase II	5	18.9×	2e-03
protein import into nucleus	5	10.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	33
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
973504	NM_005917.4(MDH1):c.359C>T (p.Ala120Val)	Pathogenic

SpliceAI

1531 predictions. Top by Δscore:

Variant	Effect	Δscore
2:63594486:A:AG	acceptor_gain	1.0000
2:63594486:AGTCT:A	acceptor_gain	1.0000
2:63594487:G:GA	acceptor_gain	1.0000
2:63594487:GTCT:G	acceptor_gain	1.0000
2:63594487:GTCTG:G	acceptor_gain	1.0000
2:63594582:ATCAG:A	donor_loss	1.0000
2:63594583:TCAGG:T	donor_loss	1.0000
2:63594586:GG:G	donor_loss	1.0000
2:63594587:G:A	donor_loss	1.0000
2:63594588:T:C	donor_loss	1.0000
2:63597390:T:G	acceptor_gain	1.0000
2:63597396:CA:C	acceptor_loss	1.0000
2:63597397:A:AC	acceptor_loss	1.0000
2:63597397:A:AG	acceptor_gain	1.0000
2:63597398:G:GA	acceptor_gain	1.0000
2:63597398:GAT:G	acceptor_gain	1.0000
2:63597479:G:T	donor_gain	1.0000
2:63597549:A:G	donor_gain	1.0000
2:63597562:G:GT	donor_gain	1.0000
2:63597562:GAA:G	donor_gain	1.0000
2:63597565:G:GG	donor_gain	1.0000
2:63597570:T:G	donor_gain	1.0000
2:63597571:TAAG:T	donor_loss	1.0000
2:63597572:AAGGT:A	donor_loss	1.0000
2:63597573:AGG:A	donor_loss	1.0000
2:63597576:T:A	donor_loss	1.0000
2:63599165:CCTAG:C	acceptor_loss	1.0000
2:63599167:TA:T	acceptor_loss	1.0000
2:63599169:GGTT:G	acceptor_gain	1.0000
2:63599288:CTCAA:C	donor_gain	1.0000

AlphaMissense

2187 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:63594516:G:A	G11E	1.000
2:63595486:G:A	E56K	1.000
2:63595495:G:C	D59H	1.000
2:63597474:G:C	R92T	1.000
2:63597475:A:C	R92S	1.000
2:63597475:A:T	R92S	1.000
2:63597514:T:A	N105K	1.000
2:63597514:T:G	N105K	1.000
2:63599182:G:C	G130R	1.000
2:63599183:G:A	G130D	1.000
2:63599183:G:T	G130V	1.000
2:63599187:T:A	N131K	1.000
2:63599187:T:G	N131K	1.000
2:63599189:C:A	P132Q	1.000
2:63599196:T:A	N134K	1.000
2:63599196:T:G	N134K	1.000
2:63599267:T:C	L158S	1.000
2:63599269:G:C	D159H	1.000
2:63599270:A:C	D159A	1.000
2:63599270:A:T	D159V	1.000
2:63604747:T:A	W184R	1.000
2:63604747:T:C	W184R	1.000
2:63604750:G:A	G185R	1.000
2:63604750:G:C	G185R	1.000
2:63604751:G:A	G185E	1.000
2:63604751:G:T	G185V	1.000
2:63604755:C:A	N186K	1.000
2:63604755:C:G	N186K	1.000
2:63604756:C:G	H187D	1.000
2:63604758:T:A	H187Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000120364 (2:63592263 A>G), RS1000241824 (2:63591893 TG>T), RS1000315793 (2:63606190 G>A), RS1000368035 (2:63606618 G>A,T), RS1000377093 (2:63607466 G>A), RS1000523680 (2:63600553 T>A), RS1000590387 (2:63598817 G>T), RS1000653694 (2:63607541 A>C,T), RS1000705920 (2:63607691 G>A,T), RS1000788305 (2:63605399 G>A), RS1001009378 (2:63593673 C>T), RS1001110043 (2:63587689 C>T), RS1001652076 (2:63592973 G>A), RS1001657913 (2:63607062 A>C,G), RS1001722583 (2:63607262 C>A,T)

Disease associations

OMIM: gene MIM:154200 | disease phenotypes: MIM:618959

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 88	Moderate	Autosomal recessive

Mondo (1): developmental and epileptic encephalopathy, 88 (MONDO:0030072)

Orphanet (0):

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000232	Everted lower lip vermilion
HP:0000253	Progressive microcephaly
HP:0000348	High forehead
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001338	Partial agenesis of the corpus callosum
HP:0001510	Growth delay
HP:0002521	Hypsarrhythmia
HP:0005280	Depressed nasal bridge
HP:0007068	Inferior cerebellar vermis hypoplasia
HP:0008936	Axial hypotonia
HP:0012110	Hypoplasia of the pons
HP:0100876	Infra-orbital crease
HP:0200134	Epileptic encephalopathy
HP:0500149	Hyperglutamatemia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006585_2593	Blood protein levels	2.000000e-08
GCST007327_151	Smoking status (ever vs never smokers)	6.000000e-09
GCST008919_6	Asthma and attention deficit hyperactivity disorder	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3560 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 195,492 (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
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1221	SULCONAZOLE	4	12,121
CHEMBL1484	NICARDIPINE	4	30,866
CHEMBL593	DELAVIRDINE	4	25,453
CHEMBL808	ECONAZOLE	4	24,813
CHEMBL91	MICONAZOLE	4	45,914

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

ChEMBL bioactivities

20 potent at pChembl≥5 of 30 total, top 20 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.13	Ki	740	nM	CHEMBL4068781
6.04	IC50	920	nM	CHEMBL4096306
5.97	IC50	1070	nM	CHEMBL4068781
5.96	IC50	1100	nM	CHEMBL427092
5.94	IC50	1140	nM	CHEMBL4065526
5.93	IC50	1180	nM	CHEMBL4091027
5.88	IC50	1310	nM	CHEMBL4098767
5.85	IC50	1400	nM	CHEMBL4074947
5.81	IC50	1540	nM	CHEMBL4074694
5.64	IC50	2270	nM	CHEMBL4068233
5.61	IC50	2430	nM	CHEMBL4087903
5.52	IC50	3000	nM	CHEMBL4095380
5.52	IC50	3000	nM	CHEMBL4099949
5.46	IC50	3440	nM	CHEMBL4073085
5.32	IC50	4740	nM	CHEMBL4086789
5.29	IC50	5160	nM	CHEMBL4080721
5.18	IC50	6650	nM	CHEMBL4105436
5.17	IC50	6780	nM	CHEMBL242020
5.17	IC50	6790	nM	CHEMBL4085170
5.02	IC50	9580	nM	CHEMBL4078740

PubChem BioAssay actives

20 with measured affinity, of 121 total; 19 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
methyl 3-[3-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]propanoylamino]benzoate	1476504: Competitive inhibition of human MDH1 expressed in Escherichia coli using oxaloacetic acid as substrate in presence of NADH after 30 mins by double reciprocal plot analysis	ki	0.7400	uM
prop-2-ynyl 4-hydroxy-3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	0.9200	uM
methyl 3-[[2-[4-(1-adamantyl)phenoxy]acetyl]amino]-4-hydroxybenzoate	1476498: Inhibition of MDH1 (unknown origin)	ic50	1.1000	uM
methyl 4-hydroxy-3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.1400	uM
methyl 3-[4-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]butanoylamino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.1800	uM
methyl 3-[[2-[4-(1-adamantyl)phenoxy]-2-methylpropanoyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.3100	uM
methyl 3-[[2-methyl-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]propanoyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.4000	uM
methyl 4-hydroxy-3-[3-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]propanoylamino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	1.5400	uM
methyl 4-methoxy-3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	2.2700	uM
methyl 4-prop-2-ynoxy-3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	2.4300	uM
N-[4-(4-methylpiperazin-1-yl)phenyl]-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetamide	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	3.0000	uM
methyl 4-hydroxy-3-[[2-methyl-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]propanoyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	3.0000	uM
N-[4-(trifluoromethyl)phenyl]-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetamide	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	3.4400	uM
1-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanone	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	4.7400	uM
methyl 4-hydroxy-3-[4-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]butanoylamino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	5.1600	uM
methyl 3-[[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	6.6500	uM
2-[4-[2-[5-hydroxy-2-[(4-methoxyphenyl)methylcarbamoyl]-4-oxochromen-7-yl]oxyethyl]-2-methoxyanilino]-2-oxoacetic acid	747626: Inhibition of human recombinant carboxy-terminal his-tagged MDH-1 (3 to 334) expressed in Escherichia coli using oxaloacetic acid as substrate after 10 mins by UV endpoint analysis	ic50	6.7800	uM
methyl 3-[[2-(4-pentylphenoxy)acetyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	6.7900	uM
methyl 3-[[2-(4-butylphenoxy)acetyl]amino]benzoate	1476476: Inhibition of human MDH1 expressed in Escherichia coli after 30 mins by oxaloacetate-dependent NADH oxidation assay	ic50	9.5800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression, affects expression	5
bisphenol A	affects expression, decreases expression, increases expression	4
Cyclosporine	decreases expression	3
trichostatin A	affects cotreatment, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Hydrogen Peroxide	affects cotreatment, increases expression, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
bismuth tripotassium dicitrate	increases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
arsenite	affects binding, increases reaction	1
2,6-dichloro-4-nitrophenol	decreases expression	1
malic acid	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
artenimol	affects binding	1
epigallocatechin gallate	decreases expression	1
dinophysistoxin 1	decreases expression	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
obeticholic acid	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2384177	Binding	Inhibition of human recombinant carboxy-terminal his-tagged MDH-1 (3 to 334) expressed in Escherichia coli using oxaloacetic acid as substrate after 10 mins by UV endpoint analysis	Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XQ35	HAP1 MDH1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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