SORD

Summary

SORD (sorbitol dehydrogenase, HGNC:11184) is a protein-coding gene on chromosome 15q21.1, encoding Sorbitol dehydrogenase (Q00796). Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols.

Sorbitol dehydrogenase (SORD; EC 1.1.1.14) catalyzes the interconversion of polyols and their corresponding ketoses, and together with aldose reductase (ALDR1; MIM 103880), makes up the sorbitol pathway that is believed to play an important role in the development of diabetic complications (summarized by Carr and Markham, 1995 [PubMed 8535074]). The first reaction of the pathway (also called the polyol pathway) is the reduction of glucose to sorbitol by ALDR1 with NADPH as the cofactor. SORD then oxidizes the sorbitol to fructose using NAD(+) cofactor.

Source: NCBI Gene 6652 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 1,198 total — 27 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003104

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11184
Approved symbol	SORD
Name	sorbitol dehydrogenase
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Aliases	SDH, XDH
Ensembl gene	ENSG00000140263
Ensembl biotype	protein_coding
OMIM	182500
Entrez	6652

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 10 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000267814, ENST00000558574, ENST00000558580, ENST00000558789, ENST00000559230, ENST00000559562, ENST00000560488, ENST00000674211, ENST00000674368, ENST00000674387, ENST00000674405, ENST00000674487, ENST00000889812, ENST00000889813, ENST00000889814, ENST00000889815, ENST00000889816, ENST00000889817, ENST00000889818, ENST00000915901

RefSeq mRNA: 1 — MANE Select: NM_003104 NM_003104

CCDS: CCDS10116

Canonical transcript exons

ENST00000267814 — 9 exons

Exon	Start	End
ENSE00001121766	45061067	45061226
ENSE00001121776	45043257	45043421
ENSE00001121784	45040408	45040441
ENSE00001140428	45073365	45077185
ENSE00002548215	45023195	45023349
ENSE00003562386	45068181	45068246
ENSE00003587170	45072317	45072438
ENSE00003620190	45065271	45065389
ENSE00003677720	45068877	45069052

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 97.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.2212 / max 750.7028, expressed in 1776 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146421	26.5824	1775
207496	0.4233	212
146420	0.2154	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	97.93	gold quality
left lobe of thyroid gland	UBERON:0001120	97.74	gold quality
thyroid gland	UBERON:0002046	97.51	gold quality
right lobe of liver	UBERON:0001114	97.37	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.09	gold quality
prostate gland	UBERON:0002367	91.67	gold quality
right adrenal gland cortex	UBERON:0035827	91.38	gold quality
right adrenal gland	UBERON:0001233	91.34	gold quality
liver	UBERON:0002107	90.29	gold quality
left adrenal gland	UBERON:0001234	90.02	gold quality
left adrenal gland cortex	UBERON:0035825	89.80	gold quality
islet of Langerhans	UBERON:0000006	89.60	gold quality
ventricular zone	UBERON:0003053	89.01	gold quality
gall bladder	UBERON:0002110	88.12	gold quality
adrenal gland	UBERON:0002369	87.45	gold quality
adrenal cortex	UBERON:0001235	87.30	gold quality
adult mammalian kidney	UBERON:0000082	86.42	gold quality
nasal cavity mucosa	UBERON:0001826	86.27	gold quality
skin of abdomen	UBERON:0001416	85.81	gold quality
rectum	UBERON:0001052	85.66	gold quality
embryo	UBERON:0000922	85.64	gold quality
ganglionic eminence	UBERON:0004023	85.64	gold quality
lower esophagus mucosa	UBERON:0035834	85.49	gold quality
stromal cell of endometrium	CL:0002255	85.22	gold quality
esophagus mucosa	UBERON:0002469	84.95	gold quality
body of stomach	UBERON:0001161	83.99	gold quality
skin of leg	UBERON:0001511	83.93	gold quality
sural nerve	UBERON:0015488	83.24	gold quality
nasal cavity epithelium	UBERON:0005384	83.11	gold quality
adrenal tissue	UBERON:0018303	83.08	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	233.37
E-MTAB-10287	yes	48.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, PLAGL1

miRNA regulators (miRDB)

77 targeting SORD, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-6083	99.47	68.73	2393

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• crystals of sorbitol dehydrogenase belong to the monoclinic C2 space group, with unit-cell parameters a = 145.9, b = 52.3, c = 169.0 A, beta = 101.8 degrees (PMID:12595725)
• Sorbitol dehydrogenase (SDH), a member of the medium-chain dehydrogenase/reductase protein family and the second enzyme of the polyol pathway of glucose metabolism, converts sorbitol to fructose strictly using NAD(+) as coenzyme. (PMID:14965227)
• Results compare the catalytic mechanism of liver sorbitol dehydrogenase with wild-type and Glu154–>Cys forms of yeast xylitol dehydrogenase. (PMID:17343568)
• The zinc-finger protein ZAC1 is up-regulated under hypertonic stress and negatively regulates expression of sorbitol dehydrogenase, allowing for accumulation of sorbitol as a compatible organic osmolyte. (PMID:19423711)
• The expression of SORD is regulated by androgens in human prostate. In prostate cancer, increased immunostaining was associated with high Gleason patterns and high serum PSA concentrations. (PMID:20372835)
• The SDH level was significantly decreased in patients with proliferative compared with non-proliferative retinopathy in both insulin and oral diabetic groups. (PMID:23452182)
• Thus, our findings suggest that the -888G > C polymorphism in the SORD gene is not involved in the pathogenesis of diabtic retinopathy in type 2 diabetes. (PMID:23850972)
• One of the most striking changes involved sorbitol dehydrogenase, a key enzyme in the polyol pathway. Validation studies revealed dramatically increased sorbitol dehydrogenase concentrations and activity in adenomas and cancer cell lines, along with important changes in the expression of other enzymes in the same (AKR1B1) and related (KHK) pathways. (PMID:24567419)
• SDH gene expression was increased by hypoxia and oxidative stress, but not extracellular hyperosmolarity. Hyperosmolarity and hypoxia did not alter the SDH protein level. (PMID:27628063)
• ALR2 rs759853 and SDH rs2055858 polymorphisms were respectively associated with a higher and lower risk of diabetic retinopathy. (PMID:31539366)
• Evaluation of SORD mutations as a novel cause of Charcot-Marie-Tooth disease. (PMID:33314640)
• Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients. (PMID:33875678)
• Association of SORD mutation with autosomal recessive asymmetric distal hereditary motor neuropathy. (PMID:35436891)
• Hereditary polyneuropathy with conduction block associated with SORD mutation in three siblings. (PMID:37418112)
• Expanding the genetic and clinical spectrum of SORD-related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement. (PMID:37584201)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	sord	ENSDARG00000053405
mus_musculus	Sord	ENSMUSG00000027227
rattus_norvegicus	Sord	ENSRNOG00000017291
drosophila_melanogaster	Sodh2	FBGN0022359
drosophila_melanogaster	Sodh1	FBGN0024289
caenorhabditis_elegans		WBGENE00011003
caenorhabditis_elegans		WBGENE00011004

Paralogs (17): PTGR1 (ENSG00000106853), VAT1 (ENSG00000108828), TP53I3 (ENSG00000115129), MECR (ENSG00000116353), CRYZ (ENSG00000116791), RTN4IP1 (ENSG00000130347), PTGR2 (ENSG00000140043), VAT1L (ENSG00000171724), ADH6 (ENSG00000172955), PTGR3 (ENSG00000180011), ADH1A (ENSG00000187758), ADH7 (ENSG00000196344), ADH1B (ENSG00000196616), ADH5 (ENSG00000197894), ADH4 (ENSG00000198099), CRYZL1 (ENSG00000205758), ADH1C (ENSG00000248144)

Protein

Protein identifiers

Sorbitol dehydrogenase — Q00796 (reviewed: Q00796)

Alternative names: (R,R)-butanediol dehydrogenase, L-iditol 2-dehydrogenase, Polyol dehydrogenase, Ribitol dehydrogenase, Xylitol dehydrogenase

All UniProt accessions (4): Q00796, A0A6I8PIS1, A0A6I8PRA7, H0YKB3

UniProt curated annotations — full annotation on UniProt →

Function. Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols. Is mostly active with D-sorbitol (D-glucitol), L-threitol, xylitol and ribitol as substrates, leading to the C2-oxidized products D-fructose, L-erythrulose, D-xylulose, and D-ribulose, respectively. Is a key enzyme in the polyol pathway that interconverts glucose and fructose via sorbitol, which constitutes an important alternate route for glucose metabolism. The polyol pathway is believed to be involved in the etiology of diabetic complications, such as diabetic neuropathy and retinopathy, induced by hyperglycemia. May play a role in sperm motility by using sorbitol as an alternative energy source for sperm motility. May have a more general function in the metabolism of secondary alcohols since it also catalyzes the stereospecific oxidation of (2R,3R)-2,3-butanediol. To a lesser extent, can also oxidize L-arabinitol, galactitol and D-mannitol and glycerol in vitro. Oxidizes neither ethanol nor other primary alcohols. Cannot use NADP(+) as the electron acceptor.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion membrane. Cell projection. Cilium. Flagellum.

Tissue specificity. Expressed in liver. Expressed in kidney and epithelial cells of both benign and malignant prostate tissue. Expressed in epididymis (at protein level).

Disease relevance. Neuronopathy, distal hereditary motor, autosomal recessive 8 (HMNR8) [MIM:618912] An autosomal recessive disorder characterized by motor axonal neuropathy, slowly progressive distal muscle weakness mainly affecting the lower limbs, difficulty walking, and increased serum sorbitol. Additional variable features are distal sensory impairment, upper limb tremor, scoliosis, and mild hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by CP-166,572, an inhibitor that is competitive with fructose. Also competitively inhibited by phenanthroline and 4-methylpyrazole in vitro.

Cofactor. Binds 1 zinc ion per subunit.

Induction. Up-regulated by androgens and down-regulated by castration.

Similarity. Belongs to the zinc-containing alcohol dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q00796-1	1	yes
Q00796-2	2

RefSeq proteins (1): NP_003095* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002328	ADH_Zn_CS	Conserved_site
IPR011032	GroES-like_sf	Homologous_superfamily
IPR013149	ADH-like_C	Domain
IPR013154	ADH-like_N	Domain
IPR020843	ER	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR045306	SDH-like	Family

Pfam: PF00107, PF08240

Enzyme classification (BRENDA):

• EC 1.1.1.14 — L-iditol 2-dehydrogenase (BRENDA: 30 organisms, 96 substrates, 136 inhibitors, 100 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
D-SORBITOL	0.0032–785	20
NAD+	0.041–0.6	14
D-FRUCTOSE	1–1500	13
NADH	0.007–0.28	8
D-XYLITOL	0.17–37	7
D-GALACTITOL	1.5–500	4
D-RIBITOL	1.3–125	4
D-MANNITOL	16–555	3
D-RIBULOSE	34–260	3
L-IDITOL	9–20	3
L-SORBOSE	110–800	3
D-GLUCITOL	6.2–9.1	2
D-TAGATOSE	10–13	2
2-HYDROXYACETOPHENONE	0.8	1
3-DEOXY-D-SORBITOL	1.9	1

Catalyzed reactions (Rhea), 6 shown:

• L-iditol + NAD(+) = keto-L-sorbose + NADH + H(+) (RHEA:10160)
• ribitol + NAD(+) = D-ribulose + NADH + H(+) (RHEA:20053)
• xylitol + NAD(+) = D-xylulose + NADH + H(+) (RHEA:20433)
• (R,R)-butane-2,3-diol + NAD(+) = (R)-acetoin + NADH + H(+) (RHEA:24340)
• keto-D-fructose + NADH + H(+) = D-sorbitol + NAD(+) (RHEA:33031)
• L-threitol + NAD(+) = L-erythrulose + NADH + H(+) (RHEA:48760)

UniProt features (65 total): strand 17, helix 14, binding site 12, sequence variant 10, sequence conflict 5, modified residue 3, splice variant 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1PL8	X-RAY DIFFRACTION	1.9
1PL6	X-RAY DIFFRACTION	2
1PL7	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00796-F1	98.06	0.98

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 (12): 273–275; 297–299; 299; 300; 45; 51; 70; 71; 156; 184; 204; 209

Post-translational modifications (3): 2, 211, 225

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5652227	Fructose biosynthesis
R-HSA-5661270	Formation of xylulose-5-phosphate

MSigDB gene sets: 634 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, MODULE_172, MODULE_93, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, MODULE_45, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_POLYOL_CATABOLIC_PROCESS

GO Biological Process (8): glucose metabolic process (GO:0006006), D-sorbitol catabolic process (GO:0006062), obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate (GO:0019640), flagellated sperm motility (GO:0030317), fructose biosynthetic process (GO:0046370), xylitol catabolic process (GO:0051160), xylitol metabolic process (GO:0051164), D-sorbitol metabolic process (GO:0006060)

GO Molecular Function (12): (R,R)-butanediol dehydrogenase activity (GO:0000721), L-iditol 2-dehydrogenase (NAD+) activity (GO:0003939), zinc ion binding (GO:0008270), carbohydrate binding (GO:0030246), identical protein binding (GO:0042802), D-xylulose reductase activity (GO:0046526), ribitol 2-dehydrogenase (NAD+) activity (GO:0050255), NAD binding (GO:0051287), alcohol dehydrogenase (NAD+) activity (GO:0004022), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), metal ion binding (GO:0046872)

GO Cellular Component (9): obsolete extracellular space (GO:0005615), cytosol (GO:0005829), membrane (GO:0016020), motile cilium (GO:0031514), mitochondrial membrane (GO:0031966), extracellular exosome (GO:0070062), mitochondrion (GO:0005739), cilium (GO:0005929), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Fructose metabolism	1
Metabolism of carbohydrates and carbohydrate derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	3
cellular anatomical structure	3
cytoplasm	2
hexose metabolic process	1
D-sorbitol metabolic process	1
hexitol catabolic process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
fructose metabolic process	1
hexose biosynthetic process	1
pentitol catabolic process	1
xylitol metabolic process	1
pentitol metabolic process	1
hexitol metabolic process	1
alcohol dehydrogenase (NAD+) activity	1
transition metal ion binding	1
binding	1
protein binding	1
hexitol dehydrogenase activity	1
adenyl nucleotide binding	1
alcohol dehydrogenase [NAD(P)+] activity	1
catalytic activity	1
oxidoreductase activity, acting on CH-OH group of donors	1
cation binding	1
cilium	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

3732 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SORD	AKR1B1	P15121	974
SORD	XYLB	O75191	916
SORD	RDH10	Q8IZV5	886
SORD	SDR9C7	Q8NEX9	656
SORD	TALDO1	P37837	646
SORD	H6PD	O95479	645
SORD	GPT	P24298	645
SORD	KHK	P50053	597
SORD	TPI1	P00938	591
SORD	TKT	P29401	588
SORD	TKTL2	Q9H0I9	587
SORD	TKTL1	P51854	586
SORD	PYGL	P06737	576
SORD	TUFM	P49411	576
SORD	RDH8	Q9NYR8	569

IntAct

44 interactions, top by confidence:

A	B	Type	Score
SORD	SORD	psi-mi:“MI:0915”(physical association)	0.800
SORD	GCD7	psi-mi:“MI:0915”(physical association)	0.560
GCD7	SORD	psi-mi:“MI:0915”(physical association)	0.560
PRR11	NVL	psi-mi:“MI:0914”(association)	0.530
SORD	RELA	psi-mi:“MI:0915”(physical association)	0.370
ANLN	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PDLIM7	TPM1	psi-mi:“MI:0914”(association)	0.350
CFAP97	CSNK2A1	psi-mi:“MI:0914”(association)	0.350
MYH9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
NBEAL2	HAX1	psi-mi:“MI:0914”(association)	0.350
SPATA1	ANKHD1	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
PRKCE	PRPSAP2	psi-mi:“MI:0914”(association)	0.350
CAV1	PPM1G	psi-mi:“MI:0914”(association)	0.350
PRKD1	MYO1C	psi-mi:“MI:0914”(association)	0.350
KLF9	TPM3	psi-mi:“MI:0914”(association)	0.350
	KRAS	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DND1	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (139): SORD (Two-hybrid), SORD (Affinity Capture-MS), SORD (Two-hybrid), AKR1B1 (Co-fractionation), CAT (Co-fractionation), FAHD1 (Co-fractionation), FAHD2A (Co-fractionation), GPI (Co-fractionation), NIT2 (Co-fractionation), PGM1 (Co-fractionation), SORD (Co-fractionation), SORD (Co-fractionation), SORD (Co-fractionation), SORD (Co-fractionation), SORD (Co-fractionation)

ESM2 similar proteins: A0A072VPZ8, A0A0U4BHM2, A0A1B1FHP3, A0A2P1GIW4, A0A385XI11, A1CFY8, A1D9C9, A2QAC0, A2QY54, B0YC65, B6HI95, C5FTT1, C5J3R8, O22380, O49482, O74685, P07846, P0CL53, P0DMQ6, P22144, P27867, P31656, P32771, P35497, P36624, P38113, P42495, P44557, P50746, Q00796, Q06099, Q07786, Q07993, Q0CWQ2, Q17334, Q17335, Q1PSI9, Q2KNL5, Q38707, Q4WAU7

Diamond homologs: A0A385XI11, A1CFY8, A1D9C9, A2QAC0, A2QY54, A9CES3, B0YC65, B6HI95, B6YTJ5, C5FTT1, C5J3R8, O31776, O34788, O35045, O58389, P07846, P0A4X1, P0DMQ6, P0DOW0, P0DXZ0, P22144, P23991, P27867, P35497, P36624, P42327, P49645, P77280, P80338, P9WQC4, P9WQC5, Q00796, Q02912, Q06004, Q07786, Q07993, Q0CWQ2, Q1PSI9, Q29318, Q2FJ31

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1198 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	34
Uncertain significance	607
Likely benign	273
Benign	148

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027672	NM_000379.4(XDH):c.2751del (p.Gln919fs)	Pathogenic
1075330	NM_000379.4(XDH):c.1343_1350del (p.Glu448fs)	Pathogenic
1369362	NM_000379.4(XDH):c.2164A>T (p.Lys722Ter)	Pathogenic
1451493	NM_000379.4(XDH):c.598G>T (p.Glu200Ter)	Pathogenic
1457782	NM_000379.4(XDH):c.641del (p.Pro214fs)	Pathogenic
1678863	NM_003104.6(SORD):c.298C>T (p.Arg100Ter)	Pathogenic
2015541	NM_000379.4(XDH):c.3711del (p.Ile1238fs)	Pathogenic
2073968	NM_000379.4(XDH):c.1664dup (p.Ala556fs)	Pathogenic
2422980	NC_000002.11:g.(?31558824)(31637532_?)del	Pathogenic
2422981	NC_000002.11:g.(?31588418)(31589011_?)del	Pathogenic
2443692	NM_003104.6(SORD):c.851T>C (p.Leu284Pro)	Pathogenic
2731116	NM_000379.4(XDH):c.2473C>T (p.Arg825Ter)	Pathogenic
2743120	NM_000379.4(XDH):c.134del (p.Glu45fs)	Pathogenic
2744635	NM_000379.4(XDH):c.575C>A (p.Ser192Ter)	Pathogenic
2868102	NM_000379.4(XDH):c.547C>T (p.Gln183Ter)	Pathogenic
2918237	NM_000379.4(XDH):c.2751dup (p.Pro918fs)	Pathogenic
2955	NM_000379.4(XDH):c.2567del (p.Thr856fs)	Pathogenic
3026551	NM_003104.6(SORD):c.112dup (p.Arg38fs)	Pathogenic
3247316	NC_000002.11:g.(?31621419)(31624214_?)del	Pathogenic
335758	NM_000379.4(XDH):c.3847C>T (p.Arg1283Ter)	Pathogenic
4278599	NM_003104.6(SORD):c.908+1G>C	Pathogenic
4728699	NM_000379.4(XDH):c.1418_1424dup (p.Lys476fs)	Pathogenic
570826	NM_000379.4(XDH):c.3507del (p.Gly1170fs)	Pathogenic
579351	NM_000379.4(XDH):c.2274del (p.Glu760fs)	Pathogenic
635517	NM_000379.4(XDH):c.3520-1G>C	Pathogenic
641114	NM_000379.4(XDH):c.140dup (p.Cys48fs)	Pathogenic
929257	NM_003104.6(SORD):c.895C>T (p.Arg299Ter)	Pathogenic
1179049	NM_000379.4(XDH):c.2198-2A>C	Likely pathogenic
1466652	NM_000379.4(XDH):c.3052-2A>G	Likely pathogenic
1511440	NM_000379.4(XDH):c.651+1G>A	Likely pathogenic

SpliceAI

6977 predictions. Top by Δscore:

Variant	Effect	Δscore
15:45023345:GCCTG:G	donor_gain	1.0000
15:45023349:GGT:G	donor_loss	1.0000
15:45023350:G:GA	donor_loss	1.0000
15:45023351:T:G	donor_loss	1.0000
15:45040403:TTTAG:T	acceptor_loss	1.0000
15:45040404:TTAG:T	acceptor_loss	1.0000
15:45040405:TA:T	acceptor_loss	1.0000
15:45040406:A:AG	acceptor_gain	1.0000
15:45040406:AG:A	acceptor_gain	1.0000
15:45040407:G:GA	acceptor_gain	1.0000
15:45040407:G:T	acceptor_loss	1.0000
15:45040407:GG:G	acceptor_gain	1.0000
15:45040407:GGA:G	acceptor_gain	1.0000
15:45040407:GGAGA:G	acceptor_gain	1.0000
15:45040440:TGGT:T	donor_loss	1.0000
15:45040441:GGTAA:G	donor_loss	1.0000
15:45040442:G:GG	donor_gain	1.0000
15:45040443:TAA:T	donor_loss	1.0000
15:45043253:TCA:T	acceptor_loss	1.0000
15:45043255:A:AG	acceptor_gain	1.0000
15:45043255:A:T	acceptor_loss	1.0000
15:45043256:G:GA	acceptor_loss	1.0000
15:45043256:G:GG	acceptor_gain	1.0000
15:45043256:GA:G	acceptor_gain	1.0000
15:45043256:GAGGT:G	acceptor_gain	1.0000
15:45068175:GTTTA:G	acceptor_loss	1.0000
15:45068176:TTTAG:T	acceptor_loss	1.0000
15:45068177:TTA:T	acceptor_loss	1.0000
15:45068178:TA:T	acceptor_loss	1.0000
15:45068179:A:AG	acceptor_gain	1.0000

AlphaMissense

2301 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:45043368:A:T	E71V	0.999
15:45043383:T:A	V76D	0.999
15:45061076:T:A	V92D	0.999
15:45043362:G:A	G69E	0.998
15:45043364:C:G	H70D	0.998
15:45043365:A:C	H70P	0.998
15:45043366:T:A	H70Q	0.998
15:45043366:T:G	H70Q	0.998
15:45043377:G:A	G74E	0.998
15:45061181:G:A	G127E	0.998
15:45061181:G:T	G127V	0.998
15:45061221:T:G	C140W	0.998
15:45073366:T:A	W304R	0.998
15:45073366:T:C	W304R	0.998
15:45061180:G:T	G127W	0.997
15:45073368:G:C	W304C	0.997
15:45073368:G:T	W304C	0.997
15:45043295:T:C	S47P	0.996
15:45043298:G:C	D48H	0.996
15:45043298:G:T	D48Y	0.996
15:45043362:G:T	G69V	0.996
15:45043364:C:A	H70N	0.996
15:45043364:C:T	H70Y	0.996
15:45061220:G:A	C140Y	0.996
15:45065321:C:T	S159F	0.996
15:45065326:G:T	G161W	0.996
15:45043361:G:A	G69R	0.995
15:45043361:G:C	G69R	0.995
15:45043368:A:C	E71A	0.995
15:45043368:A:G	E71G	0.995

dbSNP variants (sampled 300 via entrez): RS1000046875 (15:45051510 T>A), RS1000194613 (15:45069480 G>A,C), RS1000245290 (15:45068467 G>A,C,T), RS1000305219 (15:45033916 G>T), RS1000363957 (15:45046349 T>G), RS1000424929 (15:45034464 A>G), RS1000463548 (15:45039235 TCTC>T), RS1000517391 (15:45038172 C>A,T), RS1000585151 (15:45074535 G>A,T), RS1000699517 (15:45045187 T>C,G), RS1000878461 (15:45028659 A>G), RS1000998073 (15:45063227 A>C,G), RS1001061458 (15:45056936 T>C), RS1001099559 (15:45044841 A>T), RS1001209844 (15:45049106 G>A,C)

Disease associations

OMIM: gene MIM:182500 | disease phenotypes: MIM:603592, MIM:278300, MIM:618912

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Definitive	Autosomal recessive
neuronopathy, distal hereditary motor, autosomal recessive 8	Strong	Autosomal recessive
xanthinuria type I	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Definitive	AR

Mondo (5): xanthinuria type II (MONDO:0011346), xanthinuria type I (MONDO:0010209), neuronopathy, distal hereditary motor, autosomal recessive 8 (MONDO:0030055), neuromuscular disease (MONDO:0019056), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (5): Hereditary xanthinuria (Orphanet:3467), Xanthinuria type II (Orphanet:93602), Xanthinuria type I (Orphanet:93601), Distal muscle weakness-foot deformity-elevated sorbitol level-hereditary motor neuropathy (Orphanet:700508), Neuromuscular disease (Orphanet:68381)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000126	Hydronephrosis
HP:0000804	Xanthine nephrolithiasis
HP:0001288	Gait disturbance
HP:0001761	Pes cavus
HP:0002495	Impaired vibratory sensation
HP:0002650	Scoliosis
HP:0003198	Myopathy
HP:0003431	Decreased motor nerve conduction velocity
HP:0003534	Reduced xanthine dehydrogenase level
HP:0003537	Hypouricemia
HP:0004732	Impaired renal uric acid clearance
HP:0007078	Decreased amplitude of sensory action potentials
HP:0007328	Impaired pain sensation
HP:0008959	Distal upper limb muscle weakness
HP:0008994	Proximal lower limb muscle weakness
HP:0009053	Distal lower limb muscle weakness
HP:0010933	Hyperxanthinemia
HP:0010934	Xanthinuria
HP:0012330	Pyelonephritis
HP:0033124	Increased serum sorbitol concentration
HP:6000218	Reduced circulating xanthine oxidase activity

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001762_872	Obesity-related traits	4.000000e-06
GCST002813_9	Alzheimer’s disease in APOE e4+ carriers	2.000000e-06
GCST002934_13	Zinc levels	6.000000e-06
GCST003784_2	Multiple system atrophy	6.000000e-06
GCST006661_245	Male-pattern baldness	3.000000e-24
GCST006661_246	Male-pattern baldness	5.000000e-24
GCST008466_15	Alanine aminotransferase levels in non-alcoholic fatty liver disease	3.000000e-07
GCST008467_3	Aspartate aminotransferase levels in non-alcoholic fatty liver disease	2.000000e-07
GCST009192_2	Parahippocampal gyrus volume	1.000000e-06
GCST010726_5	Periventricular white matter hyperintensities	9.000000e-06
GCST012488_26	L1-L4 bone mineral density x serum urate levels interaction	3.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0005665	white matter hyperintensity measurement
EFO:0004531	urate measurement
EFO:0007701	spine bone mineral density

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D009468	Neuromuscular Diseases	C10.668
C562584	Xanthinuria, Type I (supp.)
C566358	Xanthinuria, Type II (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2275 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 74,669 (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
CHEMBL56337	EPALRESTAT	4	110
CHEMBL50	QUERCETIN	3	74,559

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

ChEMBL bioactivities

88 potent at pChembl≥5 of 92 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.40	IC50	4	nM	CHEMBL136420
8.40	IC50	4	nM	CHEMBL136900
8.30	IC50	5	nM	CHEMBL136680
8.22	IC50	6	nM	CHEMBL34667
8.15	IC50	7	nM	CHEMBL136103
8.15	IC50	7	nM	CHEMBL342697
8.10	IC50	8	nM	CHEMBL151486
8.00	IC50	10	nM	CHEMBL36514
8.00	IC50	10	nM	CHEMBL151017
8.00	IC50	10	nM	CHEMBL287890
7.92	IC50	12	nM	CHEMBL347716
7.92	IC50	12	nM	CHEMBL147064
7.89	IC50	13	nM	CHEMBL435428
7.80	IC50	16	nM	CHEMBL136680
7.72	IC50	19	nM	CHEMBL34965
7.72	IC50	19	nM	CHEMBL286539
7.70	IC50	20	nM	CHEMBL151615
7.64	IC50	23	nM	CHEMBL149048
7.64	IC50	23	nM	CHEMBL151439
7.62	IC50	24	nM	CHEMBL348496
7.57	IC50	27	nM	CHEMBL90344
7.55	IC50	28	nM	CHEMBL36368
7.51	IC50	31	nM	CHEMBL359089
7.50	IC50	32	nM	CHEMBL151311
7.48	IC50	33	nM	CHEMBL287890
7.47	IC50	34	nM	CHEMBL346418
7.46	IC50	35	nM	CHEMBL150642
7.44	IC50	36	nM	CHEMBL359168
7.43	IC50	37	nM	CHEMBL151764
7.40	IC50	40	nM	CHEMBL149981
7.37	IC50	43	nM	CHEMBL139187
7.36	IC50	44	nM	CHEMBL556517
7.25	Kd	56.5	nM	CHEMBL5653589
7.25	ED50	56.5	nM	CHEMBL5653589
7.23	IC50	59	nM	CHEMBL150296
7.19	IC50	64	nM	CHEMBL146805
7.17	IC50	67	nM	CHEMBL151394
7.14	IC50	72	nM	CHEMBL150734
7.10	IC50	80	nM	CHEMBL356692
7.10	IC50	80	nM	CHEMBL348427
7.10	IC50	80	nM	CHEMBL150803
7.06	IC50	87	nM	CHEMBL151605
7.03	IC50	93	nM	CHEMBL151268
7.00	IC50	99	nM	CHEMBL149409
7.00	IC50	100	nM	CHEMBL151560
6.96	IC50	110	nM	CHEMBL347575
6.92	IC50	120	nM	CHEMBL151690
6.92	IC50	120	nM	CHEMBL357712
6.89	IC50	130	nM	CHEMBL346682
6.85	IC50	140	nM	CHEMBL423753

PubChem BioAssay actives

87 with measured affinity, of 135 total; 50 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
(1R)-1-[4-[(2S,6R)-4-[2-(2,4-dimethylimidazol-1-yl)pyrimidin-4-yl]-2,6-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	226556: Concentration required for 50% for in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0040	uM
(1R)-1-[4-[(2S,6R)-2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]piperazin-1-yl]pyrimidin-2-yl]ethanol	226556: Concentration required for 50% for in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0040	uM
(1R)-1-[4-[(2R,6S)-4-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,6-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	226556: Concentration required for 50% for in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0050	uM
1-[4-[(2R,6S)-4-[2-[(1R)-1-hydroxyethyl]pyrimidin-4-yl]-2,6-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanone	203725: In vitro inhibition against human recombinant sorbitol dehydrogenase	ic50	0.0060	uM
(1R)-1-[4-[(2R,6S)-2,6-dimethyl-4-(4-phenyl-1,3,5-triazin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	226556: Concentration required for 50% for in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0070	uM
(1R)-1-[4-[(2S,6R)-2,6-dimethyl-4-(4-methyl-1,3,5-triazin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	226556: Concentration required for 50% for in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0070	uM
(1R)-1-[4-[4-(3-methylquinoxalin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0080	uM
(1R)-1-[4-[(2S,6R)-4-[2-(2-hydroxyethyl)pyrimidin-4-yl]-2,6-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0100	uM
(1R)-1-[4-[(3S,5R)-4-[2-[(1R)-1-hydroxyethyl]pyrimidin-4-yl]-3,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203725: In vitro inhibition against human recombinant sorbitol dehydrogenase	ic50	0.0100	uM
(1S)-1-[4-[(3S,5R)-4-[2-[(1R)-1-hydroxyethyl]pyrimidin-4-yl]-3,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	226557: Concentration required for 50% in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0100	uM
(1R)-1-[4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0120	uM
(1R)-1-[4-[(2R)-4-[2-(2-hydroxyethyl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0120	uM
(1R)-1-[4-[(2S,6R)-2,6-dimethyl-4-[2-(4-methylimidazol-1-yl)pyrimidin-4-yl]piperazin-1-yl]pyrimidin-2-yl]ethanol	226556: Concentration required for 50% for in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0130	uM
1-[4-[(3R,5S)-4-[2-[(1R)-1-hydroxyethyl]pyrimidin-4-yl]-3,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanone	203725: In vitro inhibition against human recombinant sorbitol dehydrogenase	ic50	0.0190	uM
(1R)-1-[4-[(3S,5R)-4-[2-[(1S)-1-hydroxyethyl]pyrimidin-4-yl]-3,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203724: In vitro inhibition against human recombinant Sorbitol dehydrogenase	ic50	0.0190	uM
(1R)-1-[4-[4-[4-(hydroxymethyl)-6-methylpyrimidin-2-yl]piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0200	uM
(1R)-1-[4-[(3S)-3-methyl-4-([1,3]oxazolo[5,4-c]pyridin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0230	uM
(1R)-1-[4-[4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0230	uM
(1R)-1-[4-[4-([1,3]oxazolo[5,4-c]pyridin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0240	uM
4-[2-[(1R)-1-hydroxyethyl]pyrimidin-4-yl]-N,N-dimethylpiperazine-1-sulfonamide	200761: In vitro inhibitory activity against human SDH	ic50	0.0270	uM
1-[4-[(3S,5R)-4-[2-(1-hydroxyethyl)pyrimidin-4-yl]-3,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203724: In vitro inhibition against human recombinant Sorbitol dehydrogenase	ic50	0.0280	uM
(1R)-1-[4-[4-(2,6-dimethylpyrimidin-4-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0310	uM
(1R)-1-[4-[4-([1,3]oxazolo[5,4-b]pyridin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0320	uM
(1R)-1-[4-(4-isoquinolin-1-ylpiperazin-1-yl)pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0340	uM
(1R)-1-[4-[4-(1,3-benzoxazol-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0350	uM
(1R)-1-[4-(4-quinoxalin-2-ylpiperazin-1-yl)pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0360	uM
(1R)-1-[4-[4-(1,2-benzoxazol-3-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0370	uM
(1R)-1-[4-[4-[2-(2-hydroxyethyl)pyrimidin-4-yl]piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0400	uM
(1R)-1-[4-[(2R,6S)-2,6-dimethyl-4-(4-methyl-6-phenyl-1,3,5-triazin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	226556: Concentration required for 50% for in vitro activity against human SDH (sorbitol dehydrogenase)	ic50	0.0430	uM
(1R)-1-[4-(4-quinolin-2-ylpiperazin-1-yl)pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0440	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149468: Binding affinity to human SORD incubated for 45 mins by Kinobead based pull down assay	kd	0.0565	uM
(1R)-1-[4-[(2S)-4-[2-(2-hydroxyethyl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0590	uM
[4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]pyrimidin-2-yl]methanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0640	uM
(1R)-1-[4-[4-(4-phenylpyrimidin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0670	uM
(1R)-1-[4-[4-[4,6-di(propan-2-yl)pyrimidin-2-yl]piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0720	uM
(1R)-1-[4-[(3S)-4-[4-(hydroxymethyl)-6-methylpyrimidin-2-yl]-3-methylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0800	uM
(1R)-1-[4-[4-(4,6-diethylpyrimidin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0800	uM
(1R)-1-[4-[4-([1,3]oxazolo[4,5-c]pyridin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0800	uM
[4-(4-quinolin-2-ylpiperazin-1-yl)pyrimidin-2-yl]methanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0870	uM
[4-[4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl]pyrimidin-2-yl]methanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0930	uM
(1R)-1-[4-[(3S)-3-methyl-4-quinoxalin-2-ylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.0990	uM
(1R)-1-[4-[(2S,6R)-4-[4-(hydroxymethyl)-6-methylpyrimidin-2-yl]-2,6-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1000	uM
(1R)-1-[4-[4-(4-methylpyrimidin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1100	uM
[4-[4-(1,2-benzoxazol-3-yl)piperazin-1-yl]pyrimidin-2-yl]methanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1200	uM
(1R)-1-[4-[4-(6,7-dichloroquinoxalin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1200	uM
(1R)-1-[4-[(3S,5R)-4-[4-(hydroxymethyl)-6-methylpyrimidin-2-yl]-3,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1300	uM
(1R)-1-[4-[(3R)-4-[4-(hydroxymethyl)-6-methylpyrimidin-2-yl]-3-methylpiperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1400	uM
[4-[4-(2,6-dimethylpyrimidin-4-yl)piperazin-1-yl]pyrimidin-2-yl]methanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1400	uM
[4-(4-isoquinolin-1-ylpiperazin-1-yl)pyrimidin-2-yl]methanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1500	uM
(1R)-1-[4-[4-([1,3]oxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl]pyrimidin-2-yl]ethanol	203723: Concentration required for 50% in vitro inhibition of recombinant human sorbitol dehydrogenase (h-SDH)	ic50	0.1700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression	3
bisphenol A	increases expression, affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Cadmium Chloride	increases expression, decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	increases expression	1
potassium chromate(VI)	increases expression	1
epalrestat	decreases reaction, increases abundance	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
bicalutamide	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
ranirestat	increases abundance, decreases reaction	1
monomethylarsonous acid	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, decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
fenbuconazole	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1

ChEMBL screening assays

17 unique, capped per target: 16 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1260799	Binding	Inhibition sorbitol dehydrogenase by spectrophotometric analysis	6,7-Dihydroxy-4-phenylcoumarin as inhibitor of aldose reductase 2. — Bioorg Med Chem Lett
CHEMBL803495	Functional	% Ability to inhibit lower sciatic nerve fructose that became elevated in diabetic nerve in streptozotocin diabetic rat model at 1 mg/kg; ND is not determined	A sorbitol dehydrogenase inhibitor of exceptional in vivo potency with a long duration of action: 1-(R)-[4-[4-(4,6-dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2- yl]ethanol. — J Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1QN	Abcam K-562 SORD KO	Cancer cell line	Female
CVCL_D2M9	Abcam Raji SORD KO	Cancer cell line	Male
CVCL_D9SN	Ubigene HEK293 SORD KO	Transformed cell line	Female
CVCL_TP99	HAP1 SORD (-) 1	Cancer cell line	Male
CVCL_WQ57	Abcam Jurkat SORD KO	Cancer cell line	Male
CVCL_XT68	HAP1 SORD (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis