D2HGDH

Summary

D2HGDH (D-2-hydroxyglutarate dehydrogenase, HGNC:28358) is a protein-coding gene on chromosome 2q37.3, encoding D-2-hydroxyglutarate dehydrogenase, mitochondrial (Q8N465). Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate.

This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features.

Source: NCBI Gene 728294 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 38
• Clinical variants (ClinVar): 437 total — 15 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 36
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_152783

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28358
Approved symbol	D2HGDH
Name	D-2-hydroxyglutarate dehydrogenase
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC25181, D2HGD, FLJ42195
Ensembl gene	ENSG00000180902
Ensembl biotype	protein_coding
OMIM	609186
Entrez	728294

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 28 protein_coding, 5 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000321264, ENST00000400769, ENST00000403782, ENST00000417686, ENST00000432449, ENST00000436747, ENST00000437164, ENST00000445308, ENST00000454048, ENST00000463932, ENST00000467427, ENST00000468064, ENST00000470343, ENST00000473126, ENST00000486953, ENST00000496252, ENST00000910512, ENST00000910513, ENST00000910514, ENST00000910515, ENST00000910516, ENST00000910517, ENST00000910518, ENST00000910519, ENST00000910520, ENST00000910521, ENST00000910522, ENST00000910523, ENST00000910524, ENST00000933139, ENST00000951630, ENST00000951631, ENST00000951632, ENST00000951633, ENST00000951634, ENST00000951635, ENST00000951636, ENST00000951637

RefSeq mRNA: 3 — MANE Select: NM_152783 NM_001287249, NM_001352824, NM_152783

CCDS: CCDS33426, CCDS74684

Canonical transcript exons

ENST00000321264 — 10 exons

Exon	Start	End
ENSE00001654176	241743622	241743815
ENSE00001697870	241735133	241735516
ENSE00001756432	241734630	241734695
ENSE00003509048	241744709	241744877
ENSE00003541534	241750151	241750294
ENSE00003573095	241751246	241751388
ENSE00003580456	241742435	241742574
ENSE00003660128	241767710	241768811
ENSE00003664838	241741033	241741090
ENSE00003786807	241755849	241756014

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 97.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.8113 / max 163.9584, expressed in 1755 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26553	8.6770	1754
26554	0.1254	42
26558	0.0089	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.87	gold quality
pancreatic ductal cell	CL:0002079	97.25	silver quality
tendon of biceps brachii	UBERON:0008188	95.51	silver quality
left lobe of thyroid gland	UBERON:0001120	95.37	gold quality
right lobe of thyroid gland	UBERON:0001119	95.22	gold quality
adenohypophysis	UBERON:0002196	95.11	gold quality
skin of abdomen	UBERON:0001416	94.79	gold quality
thyroid gland	UBERON:0002046	94.78	gold quality
pituitary gland	UBERON:0000007	94.65	gold quality
right lobe of liver	UBERON:0001114	93.96	gold quality
left ovary	UBERON:0002119	93.78	gold quality
transverse colon	UBERON:0001157	93.70	gold quality
metanephros cortex	UBERON:0010533	93.68	gold quality
endocervix	UBERON:0000458	93.57	gold quality
skin of leg	UBERON:0001511	93.52	gold quality
minor salivary gland	UBERON:0001830	93.33	gold quality
body of uterus	UBERON:0009853	93.33	gold quality
ectocervix	UBERON:0012249	93.20	gold quality
right ovary	UBERON:0002118	93.18	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.02	gold quality
mucosa of transverse colon	UBERON:0004991	93.00	gold quality
right adrenal gland	UBERON:0001233	92.98	gold quality
right adrenal gland cortex	UBERON:0035827	92.85	gold quality
body of pancreas	UBERON:0001150	92.65	gold quality
saliva-secreting gland	UBERON:0001044	92.59	gold quality
left uterine tube	UBERON:0001303	92.58	gold quality
body of stomach	UBERON:0001161	92.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.54	gold quality
esophagus mucosa	UBERON:0002469	92.44	gold quality
granulocyte	CL:0000094	92.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting D2HGDH, 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-6844	99.82	70.69	2423
HSA-MIR-198	98.70	67.32	920
HSA-MIR-663B	97.40	62.91	664
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-3654	96.43	66.55	646
HSA-MIR-7976	95.75	65.67	1186
HSA-MIR-874-3P	95.02	65.66	806

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 11)

• Two novel pathogenic mutations in D-2-hydroxyglutarate dehydrogenase gene in patient with a mild presentation and asymptomatic siblings with D-2-hydroxyglutaric aciduria with a splice error (IVS4-2A–>G) and a missense mutation (c.1315A–>G;p.Asn439Asp). (PMID:16037974)
• This enzyme assay will have utility in differentiating patients with 2-hydroxyglutaric aciduria and in assessing the residual activities linked to pathogenic mutations in the D2HGDH gene (PMID:19283509)
• We did not find evidence for mutations in the genes D2HGDH and L2HGDH as an alternative mechanism for raised 2-hydroxyglutarate levels in brain tumours (PMID:20727073)
• D2HGDH mutation is not associated with glioblastoma. (PMID:21625441)
• D2HGDH elevates alpha-KG levels via IDH2 expression modulation, influencing histone and DNA methylation, and HIF1alpha hydroxylation. D2HGDH mutants found in diffuse large B-cell lymphoma are enzymatically inert. (PMID:26178471)
• D2HGDH-GAL3ST2 is more frequently seen in prostate cancer samples, and seems to be enriched in African Americans. (PMID:27322736)
• Study presents the functional characterization of 31 D2HGDH missense variants, and the identification of 10 novel variants in a large cohort of patients with D-2-hydroxyglutaric aciduria Type I. The functional tests proved effective in classifying missense variants associated with severely impaired D-2-HGDH activity. (PMID:30908763)
• hD2HGDH directly reduces recombinant human ETF, thus establishing a metabolic link between the oxidation of D-2-hydroxyglutarate and the mitochondrial electron transport chain. (PMID:31349060)
• MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome. (PMID:32101699)
• Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C. (PMID:32386320)
• D-2-hydroxyglutarate dehydrogenase in breast carcinoma as a potent prognostic marker associated with proliferation. (PMID:34296423)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	d2hgdh	ENSDARG00000060210
mus_musculus	D2hgdh	ENSMUSG00000073609
rattus_norvegicus	D2hgdh	ENSRNOG00000019012
drosophila_melanogaster	D2hgdh	FBGN0023507
caenorhabditis_elegans		WBGENE00010055

Paralogs (2): AGPS (ENSG00000018510), LDHD (ENSG00000166816)

Protein

Protein identifiers

D-2-hydroxyglutarate dehydrogenase, mitochondrial — Q8N465 (reviewed: Q8N465)

All UniProt accessions (8): B5MCV2, Q8N465, F8WCF9, G5E9E8, H7C021, H7C0N1, H7C290, H7C3L2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate. Also catalyzes the oxidation of other D-2-hydroxyacids, such as D-malate (D-MAL) and D-lactate (D-LAC). Exhibits high activities towards D-2-HG and D-MAL but a very weak activity towards D-LAC.

Subcellular location. Mitochondrion.

Disease relevance. D-2-hydroxyglutaric aciduria 1 (D2HGA1) [MIM:600721] A rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by zinc and cobalt ions.

Similarity. Belongs to the FAD-binding oxidoreductase/transferase type 4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N465-1	1	yes
Q8N465-2	2
Q8N465-3	3

RefSeq proteins (3): NP_001274178, NP_001339753, NP_689996* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004113	FAD-bd_oxidored_4_C	Domain
IPR006094	Oxid_FAD_bind_N	Domain
IPR016164	FAD-linked_Oxase-like_C	Homologous_superfamily
IPR016166	FAD-bd_PCMH	Domain
IPR016167	FAD-bd_PCMH_sub1	Homologous_superfamily
IPR016169	FAD-bd_PCMH_sub2	Homologous_superfamily
IPR016171	Vanillyl_alc_oxidase_C-sub2	Homologous_superfamily
IPR036318	FAD-bd_PCMH-like_sf	Homologous_superfamily
IPR051264	FAD-oxidored/transferase_4	Family

Pfam: PF01565, PF02913

Enzyme classification (BRENDA):

• EC 1.1.99.39 — D-2-hydroxyglutarate dehydrogenase (BRENDA: 4 organisms, 10 substrates, 0 inhibitors, 7 Km, 7 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(R)-2-HYDROXYGLUTARATE	0.17–0.584	3
ELECTRON TRANSFER FLAVOPROTEIN	0.0047–0.0077	2
(S)-2-HYDROXYGLUTARATE	0.06	1
CYTOCHROME C	0.21	1

Catalyzed reactions (Rhea), 2 shown:

• (R)-2-hydroxyglutarate + A = 2-oxoglutarate + AH2 (RHEA:38295)
• (R)-malate + A = oxaloacetate + AH2 (RHEA:67460)

UniProt features (102 total): sequence variant 25, helix 22, strand 18, binding site 14, mutagenesis site 8, splice variant 5, turn 5, transit peptide 1, chain 1, modified residue 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6LPN	X-RAY DIFFRACTION	2.21
6LPT	X-RAY DIFFRACTION	2.62
6LPP	X-RAY DIFFRACTION	2.65
6LPQ	X-RAY DIFFRACTION	2.8
6LPX	X-RAY DIFFRACTION	2.8
6LPU	X-RAY DIFFRACTION	2.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N465-F1	92.60	0.91

Functional residue map

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

Ligand- & substrate-binding residues (14): 434; 441; 443; 475; 476; 476; 476; 386; 386; 386; 390; 390 …

Post-translational modifications (1): 101

Mutagenesis-validated functional residues (8):

Position	Phenotype
386	loss of catalytic activity.
390	significantly reduced catalytic activity.
401	loss of catalytic activity.
434	loss of catalytic activity.
441	loss of catalytic activity.
443	significantly reduced catalytic activity.
475	loss of catalytic activity.
476	loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-880009	Interconversion of 2-oxoglutarate and 2-hydroxyglutarate

MSigDB gene sets: 171 (showing top): GOBP_RESPONSE_TO_ZINC_ION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_RESPONSE_TO_METAL_ION, GOBP_RESPONSE_TO_MAGNESIUM_ION, GOBP_PROTEIN_DESTABILIZATION, CADWELL_ATG16L1_TARGETS_DN, GOBP_REGULATION_OF_PROTEIN_STABILITY, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS, GOBP_2_OXOGLUTARATE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_COBALT_ION

GO Biological Process (8): lactate metabolic process (GO:0006089), 2-oxoglutarate metabolic process (GO:0006103), malate metabolic process (GO:0006108), response to manganese ion (GO:0010042), response to zinc ion (GO:0010043), protein destabilization (GO:0031648), response to cobalt ion (GO:0032025), tartrate metabolic process (GO:1901275)

GO Molecular Function (7): zinc ion binding (GO:0008270), (R)-2-hydroxyglutarate dehydrogenase activity (GO:0051990), FAD binding (GO:0071949), catalytic activity (GO:0003824), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), flavin adenine dinucleotide binding (GO:0050660)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
dicarboxylic acid metabolic process	3
response to metal ion	3
monocarboxylic acid metabolic process	1
regulation of protein stability	1
carbohydrate metabolic process	1
transition metal ion binding	1
oxidoreductase activity, acting on CH-OH group of donors	1
flavin adenine dinucleotide binding	1
molecular_function	1
catalytic activity	1
cation binding	1
nucleotide binding	1
anion binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1708 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
D2HGDH	L2HGDH	Q9H9P8	984
D2HGDH	IDH2	P48735	934
D2HGDH	IDH1	O75874	895
D2HGDH	ADHFE1	Q8IWW8	640
D2HGDH	SLC25A1	P53007	519
D2HGDH	GCDH	Q92947	460
D2HGDH	ALKBH4	Q9NXW9	459
D2HGDH	SLITRK3	O94933	398
D2HGDH	ETFDH	Q16134	392
D2HGDH	TRA2B	P62995	379
D2HGDH	KLHL31	Q9H511	359
D2HGDH	ALDH5A1	P51649	356
D2HGDH	DDX20	Q9UHI6	348
D2HGDH	MDH2	P40926	339
D2HGDH	ERN2	Q76MJ5	336
D2HGDH	OGDH	Q02218	336

IntAct

26 interactions, top by confidence:

A	B	Type	Score
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
ZNF462	WIZ	psi-mi:“MI:0914”(association)	0.530
RAB30	UBB	psi-mi:“MI:0914”(association)	0.530
SDHB	POLG	psi-mi:“MI:0914”(association)	0.530
D2HGDH	HSPA8	psi-mi:“MI:0915”(physical association)	0.400
STK11	D2HGDH	psi-mi:“MI:0915”(physical association)	0.370
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
PFDN5	GTPBP10	psi-mi:“MI:0914”(association)	0.350
KIR2DS3	RTL8C	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
TIGIT	FAM171A2	psi-mi:“MI:0914”(association)	0.350
MRPS24	NUDT19	psi-mi:“MI:0914”(association)	0.350
DHRS4L2	ACOT7	psi-mi:“MI:0914”(association)	0.350
NUDT16	MTIF2	psi-mi:“MI:0914”(association)	0.350
YARS2	VWA8	psi-mi:“MI:0914”(association)	0.350
FAHD1	VWA8	psi-mi:“MI:0914”(association)	0.350
D2HGDH	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
NIPSNAP3A	NUDT19	psi-mi:“MI:0914”(association)	0.350
ABHD10	GAPDHS	psi-mi:“MI:0914”(association)	0.350
MYL10	BCKDK	psi-mi:“MI:0914”(association)	0.350
TIGIT	PTPRF	psi-mi:“MI:0914”(association)	0.350
TRMT1	PRORP	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
ZNF462	CALU	psi-mi:“MI:0914”(association)	0.350
RAB25	D2HGDH	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (151): D2HGDH (Affinity Capture-MS), D2HGDH (Co-fractionation), D2HGDH (Two-hybrid), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), SDHB (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), D2HGDH (Negative Genetic)

ESM2 similar proteins: A0A6N3IN21, A5GFZ6, A7MBC0, D3ZDK7, E1BNQ4, E2QUI9, I3LK75, P11172, P13439, P19971, P31754, P38918, P50336, P51175, P56602, P84850, Q0VGK3, Q15274, Q1JPD3, Q2KJF7, Q3T063, Q5BJY6, Q5E9M9, Q5FVR2, Q5I0M2, Q5PQQ1, Q5R514, Q5R824, Q60HD5, Q6PCB7, Q6SKR2, Q6XQN1, Q8CC86, Q8CHP8, Q8CIM3, Q8IVS8, Q8IW45, Q8IXI1, Q8JZV7, Q8N465

Diamond homologs: A1L258, A4VGK4, B8B7X6, H6LBS1, O23240, O29853, P0DV35, P39976, P46681, P52073, P84850, P94535, P9WIT0, P9WIT1, Q1JPD3, Q46911, Q7XI14, Q8CIM3, Q8N465, Q8X7S0, Q9C1X2, D4MUV9, P56216, Q9V778, B9ZUK6, F1QXM5, P0AEP9, P0AEQ0, P32891, Q12627, Q7TNG8, Q86WU2, Q94AX4, Q9LYD8, O97157, A0R607, Q5HQZ1, Q631P8, Q6HBI9, Q72Y09

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
D2HGDH	“up-regulates quantity”	2-oxoglutarate(2-)

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	10
Uncertain significance	186
Likely benign	116
Benign	44

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1022469	NM_152783.5(D2HGDH):c.1393del (p.Thr465fs)	Pathogenic
1480964	NM_152783.5(D2HGDH):c.1306+1del	Pathogenic
1805533	NM_152783.5(D2HGDH):c.71G>A (p.Trp24Ter)	Pathogenic
1852	NM_152783.5(D2HGDH):c.1331T>C (p.Val444Ala)	Pathogenic
1853	NM_152783.5(D2HGDH):c.440T>G (p.Ile147Ser)	Pathogenic
1854	NM_152783.5(D2HGDH):c.293-23A>G	Pathogenic
1856	NM_152783.5(D2HGDH):c.1315A>G (p.Asn439Asp)	Pathogenic
1857	NM_152783.5(D2HGDH):c.325_326dup (p.Glu110fs)	Pathogenic
1954804	NM_152783.5(D2HGDH):c.392dup (p.Asn132fs)	Pathogenic
2014046	NM_152783.5(D2HGDH):c.887_888insGG (p.Phe296fs)	Pathogenic
210809	NM_152783.5(D2HGDH):c.1027del (p.Ser343fs)	Pathogenic
3247382	NC_000002.11:g.(?242690641)(242690823_?)del	Pathogenic
572875	NM_152783.5(D2HGDH):c.642del (p.Arg215fs)	Pathogenic
579877	NM_152783.5(D2HGDH):c.1353del (p.Ser452fs)	Pathogenic
871019	NM_152783.5(D2HGDH):c.540T>G (p.Tyr180Ter)	Pathogenic
210815	NM_152783.5(D2HGDH):c.1306+2T>C	Likely pathogenic
3362676	NM_152783.5(D2HGDH):c.523G>T (p.Glu175Ter)	Likely pathogenic
3382850	NM_152783.5(D2HGDH):c.457A>G (p.Met153Val)	Likely pathogenic
4056413	NM_152783.5(D2HGDH):c.814T>C (p.Cys272Arg)	Likely pathogenic
4084883	NM_152783.5(D2HGDH):c.1420G>A (p.Ala474Thr)	Likely pathogenic
4085421	NM_152783.5(D2HGDH):c.1139A>G (p.Lys380Arg)	Likely pathogenic
4685138	NM_152783.5(D2HGDH):c.797C>T (p.Thr266Ile)	Likely pathogenic
4765381	NM_152783.5(D2HGDH):c.1421C>A (p.Ala474Glu)	Likely pathogenic
570363	NM_152783.5(D2HGDH):c.853+2T>C	Likely pathogenic
649282	NM_152783.5(D2HGDH):c.1370T>C (p.Leu457Pro)	Likely pathogenic

SpliceAI

2764 predictions. Top by Δscore:

Variant	Effect	Δscore
2:241742571:TCTGG:T	donor_loss	1.0000
2:241742572:CTGG:C	donor_loss	1.0000
2:241742575:G:GG	donor_gain	1.0000
2:241743810:G:GT	donor_gain	1.0000
2:241743813:GTG:G	donor_gain	1.0000
2:241750149:A:AG	acceptor_gain	1.0000
2:241750150:G:GG	acceptor_gain	1.0000
2:241750150:GGCT:G	acceptor_gain	1.0000
2:241750294:GGT:G	donor_loss	1.0000
2:241750295:G:GA	donor_loss	1.0000
2:241750296:T:G	donor_loss	1.0000
2:241751244:A:AG	acceptor_gain	1.0000
2:241751244:AG:A	acceptor_loss	1.0000
2:241751245:G:GG	acceptor_gain	1.0000
2:241751245:GA:G	acceptor_gain	1.0000
2:241751379:G:GT	donor_gain	1.0000
2:241751380:A:T	donor_gain	1.0000
2:241767706:CCA:C	acceptor_loss	1.0000
2:241767708:A:AG	acceptor_gain	1.0000
2:241767708:AG:A	acceptor_gain	1.0000
2:241767709:G:GT	acceptor_gain	1.0000
2:241767709:GG:G	acceptor_gain	1.0000
2:241767709:GGA:G	acceptor_gain	1.0000
2:241767709:GGAGA:G	acceptor_gain	1.0000
2:241741031:A:AG	acceptor_gain	0.9900
2:241741031:A:AT	acceptor_loss	0.9900
2:241741032:G:GG	acceptor_gain	0.9900
2:241741032:GGCT:G	acceptor_gain	0.9900
2:241741086:CTCAG:C	donor_loss	0.9900
2:241741087:TCAG:T	donor_loss	0.9900

AlphaMissense

3337 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:241743725:C:G	C198W	0.997
2:241743724:G:A	C198Y	0.996
2:241743730:T:A	I200N	0.993
2:241744756:G:C	K244N	0.993
2:241744756:G:T	K244N	0.993
2:241767724:C:G	H441D	0.993
2:241743799:T:A	V223D	0.992
2:241755865:G:T	R386M	0.992
2:241767820:A:C	S473R	0.992
2:241767822:C:A	S473R	0.992
2:241767822:C:G	S473R	0.992
2:241743635:C:G	C168W	0.989
2:241743724:G:T	C198F	0.989
2:241743754:C:A	A208D	0.989
2:241743723:T:C	C198R	0.988
2:241743740:C:A	N203K	0.988
2:241743740:C:G	N203K	0.988
2:241755865:G:C	R386T	0.988
2:241767948:G:C	K515N	0.988
2:241767948:G:T	K515N	0.988
2:241744840:T:G	C272W	0.987
2:241750237:G:C	D314H	0.987
2:241755866:G:C	R386S	0.987
2:241755866:G:T	R386S	0.987
2:241756008:C:G	H434D	0.987
2:241767827:A:T	E475V	0.987
2:241743633:T:C	C168R	0.986
2:241755917:C:A	D403E	0.986
2:241755917:C:G	D403E	0.986
2:241756010:C:A	H434Q	0.986

dbSNP variants (sampled 300 via entrez): RS1000013111 (2:241768675 C>T), RS1000027028 (2:241740281 C>G), RS1000227335 (2:241745506 C>G), RS1000417645 (2:241745728 A>G), RS1000442431 (2:241758235 A>G,T), RS1000470070 (2:241745523 A>C), RS1000643292 (2:241764041 G>A), RS1000670279 (2:241749312 G>A,T), RS1000742191 (2:241763871 G>A), RS1000839031 (2:241734979 T>A,C), RS1000902010 (2:241747111 A>C,G), RS1000969755 (2:241741938 G>A), RS1000982344 (2:241737671 G>A), RS1001033964 (2:241739362 G>A), RS1001056317 (2:241733721 G>A)

Disease associations

OMIM: gene MIM:609186 | disease phenotypes: MIM:600721

GenCC curated gene-disease

Disease	Classification	Inheritance
D-2-hydroxyglutaric aciduria 1	Strong	Autosomal recessive
D-2-hydroxyglutaric aciduria	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (2): D-2-hydroxyglutaric aciduria 1 (MONDO:0024554), D-2-hydroxyglutaric aciduria (MONDO:0010924)

Orphanet (1): D-2-hydroxyglutaric aciduria (Orphanet:79315)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000347	Micrognathia
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001638	Cardiomyopathy
HP:0001659	Aortic regurgitation
HP:0002007	Frontal bossing
HP:0002069	Bilateral tonic-clonic seizure
HP:0002104	Apnea
HP:0002119	Ventriculomegaly
HP:0002188	Delayed CNS myelination
HP:0002416	Subependymal cysts
HP:0002521	Hypsarrhythmia
HP:0002572	Episodic vomiting
HP:0003150	Glutaric aciduria
HP:0003593	Infantile onset
HP:0005348	Inspiratory stridor
HP:0006956	Lateral ventricle dilatation
HP:0007052	Multifocal cerebral white matter abnormalities
HP:0007105	Infantile encephalopathy
HP:0010307	Stridor
HP:0011220	Prominent forehead
HP:0012321	D-2-hydroxyglutaric aciduria
HP:0012448	Delayed myelination

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST003987_10	Asthma	2.000000e-15
GCST003990_7	Allergy	3.000000e-13
GCST004600_181	Eosinophil percentage of white cells	2.000000e-25
GCST004606_56	Eosinophil count	5.000000e-24
GCST004617_76	Eosinophil percentage of granulocytes	3.000000e-21
GCST004623_170	Neutrophil percentage of granulocytes	3.000000e-18
GCST004624_63	Sum eosinophil basophil counts	5.000000e-21
GCST005038_26	Allergic disease (asthma, hay fever or eczema)	4.000000e-33
GCST006911_6	Asthma (moderate or severe)	2.000000e-23
GCST007563_8	Allergic disease (asthma, hay fever or eczema)	2.000000e-15
GCST007564_30	Asthma or allergic disease (pleiotropy)	5.000000e-17
GCST007797_32	Asthma onset (childhood vs adult)	2.000000e-08
GCST007798_52	Asthma	9.000000e-52
GCST007799_41	Asthma (adult onset)	2.000000e-28
GCST007800_42	Asthma (childhood onset)	4.000000e-69
GCST007941_44	Medication use (adrenergics, inhalants)	5.000000e-28
GCST007942_17	Medication use (glucocorticoids)	2.000000e-23
GCST007943_7	Medication use (antihistamines for systemic use)	6.000000e-09
GCST007993_16	Asthma (adult onset)	2.000000e-11
GCST007995_12	Asthma (childhood onset)	2.000000e-20
GCST008525_2	Artificially sweetened beverage consumption	2.000000e-07
GCST008916_19	Asthma	4.000000e-42
GCST009647_7	Serum cancer antigen 125 (CA 125) levels	2.000000e-11
GCST009718_4	Eczema	3.000000e-09
GCST009719_6	Allergic rhinitis	3.000000e-24
GCST009720_93	Asthma	1.000000e-44
GCST009798_13	Asthma	5.000000e-36
GCST010042_117	Asthma	2.000000e-70
GCST010043_105	Asthma	2.000000e-55
GCST010984_9	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	3.000000e-13

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009942	Glucocorticoid use measurement
EFO:0009943	Antihistamine use measurement
EFO:0010096	artificially sweetened beverage consumption measurement
EFO:0010603	cancer antigen 125 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases expression, increases abundance, affects cotreatment	4
Tobacco Smoke Pollution	decreases expression	3
bisphenol A	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	increases expression, increases abundance	2
bisphenol S	increases expression, affects cotreatment, decreases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Vehicle Emissions	decreases methylation, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, increases methylation	2
bisphenol F	affects cotreatment, decreases expression	1
glycidyl methacrylate	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
alpha-hydroxyglutarate	increases metabolic processing	1
acipimox	decreases expression	1
ferrous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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