GALE

Summary

GALE (UDP-galactose-4-epimerase, HGNC:4116) is a protein-coding gene on chromosome 1p36.11, encoding UDP-glucose 4-epimerase (Q14376). Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine.

This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild (‘peripheral’ form) to severe (‘generalized’ form). Multiple alternatively spliced transcripts encoding the same protein have been identified.

Source: NCBI Gene 2582 — RefSeq curated summary.

At a glance

• Gene–disease (curated): galactose epimerase deficiency (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 432 total — 25 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001008216

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4116
Approved symbol	GALE
Name	UDP-galactose-4-epimerase
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	SDR1E1
Ensembl gene	ENSG00000117308
Ensembl biotype	protein_coding
OMIM	606953
Entrez	2582

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 15 protein_coding, 9 protein_coding_CDS_not_defined

ENST00000374497, ENST00000418277, ENST00000425913, ENST00000429356, ENST00000445705, ENST00000456977, ENST00000459934, ENST00000466250, ENST00000467070, ENST00000467493, ENST00000469556, ENST00000470383, ENST00000470949, ENST00000481736, ENST00000486382, ENST00000617979, ENST00000854947, ENST00000854948, ENST00000854949, ENST00000854950, ENST00000927392, ENST00000927393, ENST00000958001, ENST00000958002

RefSeq mRNA: 3 — MANE Select: NM_001008216 NM_000403, NM_001008216, NM_001127621

CCDS: CCDS242

Canonical transcript exons

ENST00000617979 — 12 exons

Exon	Start	End
ENSE00001372948	23799366	23799436
ENSE00003539943	23796876	23796942
ENSE00003574235	23796697	23796782
ENSE00003585254	23798887	23799012
ENSE00003598794	23797695	23797871
ENSE00003630984	23798615	23798730
ENSE00003670822	23797034	23797147
ENSE00003677372	23798117	23798230
ENSE00003730676	23795599	23796007
ENSE00003743162	23800712	23800754
ENSE00003787594	23796151	23796265
ENSE00003791424	23796509	23796586

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.9640 / max 133.6705, expressed in 1788 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11003	14.3714	1760
11004	1.9687	1202
10999	1.0916	466
11002	0.7579	457
11001	0.6546	363
11000	0.1197	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.12	gold quality
mucosa of transverse colon	UBERON:0004991	96.17	gold quality
rectum	UBERON:0001052	96.07	gold quality
right lobe of liver	UBERON:0001114	95.26	gold quality
esophagus mucosa	UBERON:0002469	95.16	gold quality
minor salivary gland	UBERON:0001830	94.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.24	gold quality
gall bladder	UBERON:0002110	94.01	gold quality
duodenum	UBERON:0002114	93.82	gold quality
body of stomach	UBERON:0001161	93.51	gold quality
metanephros cortex	UBERON:0010533	93.31	gold quality
saliva-secreting gland	UBERON:0001044	93.15	gold quality
mouth mucosa	UBERON:0003729	93.05	gold quality
stomach	UBERON:0000945	91.85	gold quality
transverse colon	UBERON:0001157	91.83	gold quality
jejunal mucosa	UBERON:0000399	91.01	gold quality
amniotic fluid	UBERON:0000173	90.85	gold quality
colonic mucosa	UBERON:0000317	89.98	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.49	gold quality
liver	UBERON:0002107	89.41	gold quality
buccal mucosa cell	CL:0002336	89.39	gold quality
small intestine	UBERON:0002108	89.30	gold quality
upper lobe of left lung	UBERON:0008952	89.24	gold quality
nasal cavity epithelium	UBERON:0005384	89.21	gold quality
mucosa of stomach	UBERON:0001199	88.98	gold quality
upper lobe of lung	UBERON:0008948	88.60	gold quality
fundus of stomach	UBERON:0001160	88.59	gold quality
esophagus squamous epithelium	UBERON:0006920	88.53	gold quality
epithelium of esophagus	UBERON:0001976	88.48	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.38
E-MTAB-9689	no	130.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting GALE, 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-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-7152-3P	99.97	67.47	849
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-1909-5P	98.94	64.01	484
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-3942-5P	98.52	69.51	1517
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-212-5P	96.83	67.43	950

Literature-anchored findings (GeneRIF, showing 18)

• study of hGALE crystal structure and demonstration that residue 307 acts as a gatekeeper mediating substrate access to the hGALE active site (PMID:15175331)
• Resulst describe the relationship among UDP-galactose 4’-epimerase activity, substrate specificity, metabolic balance, and galactose sensitivity in mammalian cells. (PMID:15701638)
• Data suggest that reduced catalytic efficiency and increased proteolytic susceptibility of UDP-galactose 4-epimerase are causative factors in type III galactosemia. (PMID:16302980)
• Disease-causing mutations result in a variety of changes to the steady-state parameters. Mostly these are changes in turnover number, kcat. The ability to dimerize is not affected, but some mutants have increased sensitivity to protease digestion. (PMID:16302980)
• Subtle biochemical and metabolic abnormalities detected in patients expressing these GALE alleles likely reflect, at least in part, the reduced enzymatic activity of the encoded GALE proteins. (PMID:18188677)
• Our observations show that altered protein stability is due to misfolding and that loss or reduction of enzyme activity is responsible for the molecular defects underlying GALE-deficiency galactosemia. (PMID:19250319)
• P.K161N-hGALE causes its effects by abolishing an important interaction between the protein and the cofactor. (PMID:22613355)
• GALE variants can be arranged into three groups depending on the severity of enzyme impairment. (PMID:23644136)
• human UDP-galactose 4’-epimerase stability is increased by variants associated with type III galactosemia but decreased by substrate and cofactor binding (PMID:25150110)
• These data indicated a critical role of GALE in maintaining cartilage homeostasis, and suggested that GALE inhibition might contribute to OA progress. (PMID:25201731)
• Data show the protein structure of GALE and its substrate binding and specificity. It is mutated in type III galactosemia. [review] (PMID:26162744)
• Mutation in UDP-galactose-4’-epimerase gene is associated with UDP-galactose-4’-epimerase deficiency. (PMID:26565537)
• we have identified GALE p.R51W, a homozygous mutation in an extended kindred including multiple individuals presenting with severe thrombocytopenia and intracranial bleeding. GALE p.R51W has reduced enzymatic activity and is thermally unstable. (PMID:30247636)
• Human UDP-galactose 4’-epimerase (GALE) is required for cell-surface glycome structure and function. (PMID:31819007)
• High GALE expression is associated with differentiation Grade of Gastric Cancer. (PMID:31827638)
• Expansion of the clinical phenotype of GALE deficiency. (PMID:34159722)
• Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis. (PMID:36395340)
• GALE variants associated with syndromic manifestations, macrothrombocytopenia, bleeding, and platelet dysfunction. (PMID:36846897)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gale	ENSDARG00000002401
mus_musculus	Gale	ENSMUSG00000028671
rattus_norvegicus	Gale	ENSRNOG00000009712
caenorhabditis_elegans	gale-1	WBGENE00008132

Paralogs (10): TGDS (ENSG00000088451), HSD3B7 (ENSG00000099377), GFUS (ENSG00000104522), GMDS (ENSG00000112699), UXS1 (ENSG00000115652), NSDHL (ENSG00000147383), SDR42E2 (ENSG00000183921), SDR42E1 (ENSG00000184860), HSD3B1 (ENSG00000203857), HSD3B2 (ENSG00000203859)

Protein

Protein identifiers

UDP-glucose 4-epimerase — Q14376 (reviewed: Q14376)

Alternative names: Galactowaldenase, UDP-N-acetylgalactosamine 4-epimerase, UDP-N-acetylglucosamine 4-epimerase, UDP-galactose 4-epimerase

All UniProt accessions (6): A0A384NL38, Q14376, Q5QPP1, Q5QPP3, Q5QPP4, Q5QPP9

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The reaction with UDP-Gal plays a critical role in the Leloir pathway of galactose catabolism in which galactose is converted to the glycolytic intermediate glucose 6-phosphate. It contributes to the catabolism of dietary galactose and enables the endogenous biosynthesis of both UDP-Gal and UDP-GalNAc when exogenous sources are limited. Both UDP-sugar interconversions are important in the synthesis of glycoproteins and glycolipids.

Subunit / interactions. Homodimer.

Disease relevance. Galactosemia 3 (GALAC3) [MIM:230350] A form of galactosemia, an inborn error of galactose metabolism typically manifesting in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycemia, renal tubular dysfunction, muscle hypotonia, sepsis and cataract. GALAC3 is an autosomal recessive form caused by galactose epimerase deficiency. It can manifest as benign, peripheral form with mild symptoms and enzymatic deficiency in circulating blood cells only. A second form, known as generalized epimerase deficiency, is characterized by undetectable levels of enzyme activity in all tissues and severe clinical features, including restricted growth and intellectual disability. The disease is caused by variants affecting the gene represented in this entry. Thrombocytopenia 13, syndromic (THC13) [MIM:620776] An autosomal recessive form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC13 patients have enlarged, gray platelets with defective function. Some affected individuals have leukopenia or anemia and pancytopenia. Additional variable features include mitral valve malformations, pyloric stenosis, and impaired intellectual development. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Carbohydrate metabolism; galactose metabolism.

Miscellaneous. Contrary to the human enzyme, the E.coli ortholog (AC P09147) does not catalyze the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. Compared to the E.coli enzyme, the sugar-binding pocket of the active site is 15% larger for the human enzyme, making it possible to accommodate the acetyl group.

Similarity. Belongs to the NAD(P)-dependent epimerase/dehydratase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14376-1	1	yes
Q14376-2	2

RefSeq proteins (3): NP_000394, NP_001008217, NP_001121093 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005886	UDP_G4E	Family
IPR016040	NAD(P)-bd_dom	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF16363

Enzyme classification (BRENDA):

• EC 5.1.3.2 — UDP-glucose 4-epimerase (BRENDA: 78 organisms, 147 substrates, 97 inhibitors, 124 Km, 88 kcat entries)
• EC 5.1.3.7 — UDP-N-acetylglucosamine 4-epimerase (BRENDA: 27 organisms, 47 substrates, 22 inhibitors, 29 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
UDP-GALACTOSE	0.035–3.9	28
UDPGALACTOSE	0.0083–1.67	18
UDP-ALPHA-D-GLUCOSE	0.06–260	14
UDP-ALPHA-D-GALACTOSE	0.03–12.9	9
UDP-GLUCOSE	0.055–1.2	9
UDP-N-ACETYL-ALPHA-D-GLUCOSAMINE	0.146–2.4	7
UDP-N-ACETYL-ALPHA-D-GLUCOSAMINE	0.519–4.4	7
UDP-D-GALACTOSE	0.057–0.29	6
UDP-GALNAC	0.16–1.07	4
UDP-GLCNAC	0.2–1.087	4
UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE	0.05–2.4	3
UDP-N-ACETYLGLUCOSAMINE	0.0011–4.4	3
UDP-GAL	0.04–0.295	2
UDP-GLC	0.055–0.37	2
UDPGLUCOSE	0.25–1.4	2

Catalyzed reactions (Rhea), 2 shown:

• UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-galactosamine (RHEA:20517)
• UDP-alpha-D-glucose = UDP-alpha-D-galactose (RHEA:22168)

UniProt features (76 total): sequence variant 22, strand 19, binding site 13, helix 12, mutagenesis site 4, turn 2, chain 1, active site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
9HI1	X-RAY DIFFRACTION	0.95
9HI0	X-RAY DIFFRACTION	1.37
9HI2	X-RAY DIFFRACTION	1.37
1EK6	X-RAY DIFFRACTION	1.5
1HZJ	X-RAY DIFFRACTION	1.5
1I3K	X-RAY DIFFRACTION	1.5
1I3L	X-RAY DIFFRACTION	1.5
1I3M	X-RAY DIFFRACTION	1.5
1I3N	X-RAY DIFFRACTION	1.5
9HJN	X-RAY DIFFRACTION	1.65
1EK5	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14376-F1	97.22	0.95

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): 157 (proton acceptor)

Ligand- & substrate-binding residues (13): 185; 206–208; 224–226; 239; 300–303; 12–14; 33–37; 66–67; 88; 92; 132–134; 161 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
81	5-fold decreased catalytic efficiency for udp-galactose epimerization.
132	loss of activity.
157	loss of activity.
307	no effect on activity towards udp-galactose. loss of activity towards udp-n-acetylgalactosamine.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5609977	Defective GALE causes EDG
R-HSA-70370	Galactose catabolism

MSigDB gene sets: 281 (showing top): MODULE_172, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, CROONQUIST_NRAS_SIGNALING_DN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, AGGCACT_MIR5153P, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_GALACTOSE_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS

GO Biological Process (3): galactose catabolic process (GO:0019388), beta-D-galactose catabolic process via UDP-galactose, Leloir pathway (GO:0033499), galactose metabolic process (GO:0006012)

GO Molecular Function (5): UDP-N-acetylglucosamine 4-epimerase activity (GO:0003974), UDP-glucose 4-epimerase activity (GO:0003978), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), isomerase activity (GO:0016853)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Diseases associated with glycosylation precursor biosynthesis	1
Metabolism of carbohydrates and carbohydrate derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
racemase and epimerase activity, acting on carbohydrates and derivatives	2
galactose metabolic process	1
hexose catabolic process	1
galactose catabolic process	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
hexose metabolic process	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GALE	CLC	Q05315	932
GALE	GALK1	P51570	923
GALE	GALT	P07902	868
GALE	GALM	Q96C23	849
GALE	UGDH	O60701	773
GALE	GNE	Q9Y223	736
GALE	UGP2	Q16851	718
GALE	GALK2	Q01415	666
GALE	GNPNAT1	Q96EK6	662
GALE	UAP1	Q16222	655
GALE	MPI	P34949	641
GALE	GPI	P06744	627
GALE	GMDS	O60547	608
GALE	PGM3	O95394	581
GALE	RBKS	Q9H477	577

IntAct

30 interactions, top by confidence:

A	B	Type	Score
GALE	GALE	psi-mi:“MI:0915”(physical association)	0.850
FAM24B	SHTN1	psi-mi:“MI:0914”(association)	0.350
POP5	RPP40	psi-mi:“MI:0914”(association)	0.350
SERBP1	UBA6	psi-mi:“MI:0914”(association)	0.350
WIF1	SMCHD1	psi-mi:“MI:0914”(association)	0.350
SYT6	SUPT5H	psi-mi:“MI:0914”(association)	0.350
DNAJB6	SCAMP1	psi-mi:“MI:0914”(association)	0.350
CA14	ORC4	psi-mi:“MI:0914”(association)	0.350
CIMIP6	DHX16	psi-mi:“MI:0914”(association)	0.350
GALE	NSF	psi-mi:“MI:0914”(association)	0.350
DACT3	GALE	psi-mi:“MI:0914”(association)	0.350
AZU1	UBA6	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DNAJC30	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
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
TTC9C		psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
FN1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
GALE	GALE	psi-mi:“MI:0915”(physical association)	0.000
	GALE	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (69): GALE (Two-hybrid), GALE (Reconstituted Complex), GALE (Two-hybrid), ACADM (Co-fractionation), ADI1 (Co-fractionation), ARMC1 (Co-fractionation), ASNS (Co-fractionation), CD2AP (Co-fractionation), ETFA (Co-fractionation), GALE (Co-fractionation), GALE (Co-fractionation), GALE (Co-fractionation), GALE (Co-fractionation), GALE (Co-fractionation), GALE (Co-fractionation)

ESM2 similar proteins: B0M3E8, E8MF10, O60547, O65780, O65781, O84903, P09147, P0AC90, P18645, P21977, P22715, P24325, P26391, P26503, P35673, P55180, P55293, P55462, P56985, P56986, P56997, P96995, Q05026, Q06952, Q14376, Q3T105, Q42605, Q43070, Q553X7, Q56093, Q564Q1, Q57301, Q59678, Q59745, Q5R8D0, Q652A8, Q7WTB1, Q8K0C9, Q8K3X3, Q8KN66

Diamond homologs: B0M3E8, E8MF10, O64749, O65780, O65781, O84903, P04397, P09147, P09609, P13226, P18645, P21977, P22715, P24325, P26503, P33119, P35673, P40801, P45602, P47364, P55180, P56600, P56985, P56986, P56997, P75517, P96995, Q05026, Q14376, Q3T105, Q42605, Q43070, Q45291, Q553X7, Q56093, Q564Q1, Q57301, Q57664, Q59083, Q59678

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GALE	“down-regulates quantity”	UDP-alpha-D-galactose(2-)	“chemical modification”
GALE	“up-regulates quantity”	UDP-alpha-D-glucose(2-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	24
Uncertain significance	114
Likely benign	210
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
197665	NM_001008216.2(GALE):c.272del (p.Leu91fs)	Pathogenic
2019974	NM_001008216.2(GALE):c.563_564del (p.Pro188fs)	Pathogenic
2059872	NM_001008216.2(GALE):c.933del (p.Ser312fs)	Pathogenic
2693656	NM_001008216.2(GALE):c.534G>A (p.Trp178Ter)	Pathogenic
2696158	NM_001008216.2(GALE):c.634_635del (p.Val212fs)	Pathogenic
2749215	NM_001008216.2(GALE):c.700del (p.Asp234fs)	Pathogenic
2801209	NM_001008216.2(GALE):c.689_690del (p.Asp229_Tyr230insTer)	Pathogenic
2822494	NM_001008216.2(GALE):c.196dup (p.Asp66fs)	Pathogenic
2843503	NM_001008216.2(GALE):c.152_155del (p.Arg51fs)	Pathogenic
2866226	NM_001008216.2(GALE):c.1A>G (p.Met1Val)	Pathogenic
2873958	NM_001008216.2(GALE):c.773dup (p.Lys259fs)	Pathogenic
2993130	NM_001008216.2(GALE):c.695_696del (p.Thr232fs)	Pathogenic
2999805	NM_001008216.2(GALE):c.815del (p.Gly272fs)	Pathogenic
3002671	NM_001008216.2(GALE):c.3G>A (p.Met1Ile)	Pathogenic
3009976	NM_001008216.2(GALE):c.655C>T (p.Arg219Ter)	Pathogenic
3067122	NM_001008216.2(GALE):c.230_231insTGTT (p.Lys78fs)	Pathogenic
3247673	NC_000001.10:g.(?24125085)(24151905_?)del	Pathogenic
3247677	NC_000001.10:g.(?24122439)(24144093_?)del	Pathogenic
3384691	NM_001008216.2(GALE):c.264del (p.Phe88fs)	Pathogenic
3646597	NM_001008216.2(GALE):c.370del (p.Gly123_Val124insTer)	Pathogenic
3677	NM_001008216.2(GALE):c.269G>A (p.Gly90Glu)	Pathogenic
3680	NM_001008216.2(GALE):c.937C>A (p.Leu313Met)	Pathogenic
4085889	NM_001008216.2(GALE):c.826_851del (p.Ser276fs)	Pathogenic
4735879	NM_001008216.2(GALE):c.753dup (p.Ile252fs)	Pathogenic
4769585	NM_001008216.2(GALE):c.781C>T (p.Gln261Ter)	Pathogenic
1066286	NM_001008216.2(GALE):c.351+1G>T	Likely pathogenic
1321343	NM_001008216.2(GALE):c.207C>A (p.Asp69Glu)	Likely pathogenic
2014728	NM_001008216.2(GALE):c.873+2T>C	Likely pathogenic
21173	NM_001008216.2(GALE):c.905G>A (p.Gly302Asp)	Likely pathogenic
2126386	NM_001008216.2(GALE):c.709+2_709+17del	Likely pathogenic

SpliceAI

1607 predictions. Top by Δscore:

Variant	Effect	Δscore
1:23796149:A:AC	donor_gain	1.0000
1:23796150:C:CC	donor_gain	1.0000
1:23796150:CA:C	donor_gain	1.0000
1:23796150:CACAT:C	donor_gain	1.0000
1:23796153:AT:A	donor_gain	1.0000
1:23796154:T:TA	donor_gain	1.0000
1:23796176:TGTC:T	donor_gain	1.0000
1:23796263:GATC:G	acceptor_loss	1.0000
1:23796264:ATC:A	acceptor_loss	1.0000
1:23796265:TC:T	acceptor_loss	1.0000
1:23796266:C:CC	acceptor_gain	1.0000
1:23796593:C:CT	acceptor_gain	1.0000
1:23796593:C:T	acceptor_gain	1.0000
1:23796682:C:CA	donor_gain	1.0000
1:23796694:TA:T	donor_loss	1.0000
1:23796695:AC:A	donor_gain	1.0000
1:23796695:ACC:A	donor_loss	1.0000
1:23796696:C:CA	donor_loss	1.0000
1:23796696:CC:C	donor_gain	1.0000
1:23796723:T:A	donor_gain	1.0000
1:23796723:T:TA	donor_loss	1.0000
1:23796779:ACAC:A	acceptor_gain	1.0000
1:23796780:CAC:C	acceptor_gain	1.0000
1:23796780:CACC:C	acceptor_gain	1.0000
1:23796781:ACC:A	acceptor_loss	1.0000
1:23796782:CCT:C	acceptor_loss	1.0000
1:23796783:C:CC	acceptor_gain	1.0000
1:23796784:T:A	acceptor_loss	1.0000
1:23796786:C:CT	acceptor_gain	1.0000
1:23796870:GCTCA:G	donor_loss	1.0000

AlphaMissense

2259 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:23797833:G:C	S130R	0.999
1:23797833:G:T	S130R	0.999
1:23797835:T:G	S130R	0.999
1:23797830:G:C	S131R	0.998
1:23797830:G:T	S131R	0.998
1:23797832:T:G	S131R	0.998
1:23796774:C:G	D240H	0.997
1:23797055:G:C	N207K	0.996
1:23797055:G:T	N207K	0.996
1:23797118:G:C	F186L	0.996
1:23797118:G:T	F186L	0.996
1:23797120:A:G	F186L	0.996
1:23798179:A:G	S97P	0.996
1:23796578:G:C	N268K	0.995
1:23796578:G:T	N268K	0.995
1:23796773:T:A	D240V	0.995
1:23796776:C:G	R239P	0.995
1:23797115:G:C	N187K	0.995
1:23797115:G:T	N187K	0.995
1:23796232:C:G	D303H	0.994
1:23796761:A:T	V244D	0.994
1:23796773:T:G	D240A	0.994
1:23797041:A:T	V212D	0.994
1:23797126:G:T	R184S	0.994
1:23796181:A:G	W320R	0.993
1:23796181:A:T	W320R	0.993
1:23796911:A:T	V225D	0.993
1:23797750:C:T	G158D	0.993
1:23797825:G:T	A133D	0.993
1:23797834:C:T	S130N	0.993

dbSNP variants (sampled 300 via entrez): RS1000138281 (1:23799429 G>A), RS1000142231 (1:23801196 G>C), RS1000581853 (1:23795229 CCT>C), RS1001194680 (1:23801490 A>T), RS1002078908 (1:23797515 C>T), RS1002430192 (1:23797301 C>T), RS1002447220 (1:23797660 C>A), RS1002817730 (1:23800438 G>C,T), RS1002887045 (1:23798047 G>A,T), RS1002902465 (1:23800996 C>T), RS1003142382 (1:23795504 T>C), RS1004146918 (1:23796326 G>T), RS1004320017 (1:23800131 G>A), RS1004597282 (1:23799501 T>C), RS1005488080 (1:23802217 G>A,T)

Disease associations

OMIM: gene MIM:606953 | disease phenotypes: MIM:230350, MIM:620776, MIM:246450

GenCC curated gene-disease

Disease	Classification	Inheritance
galactose epimerase deficiency	Definitive	Autosomal recessive
thrombocytopenia 13, syndromic	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
galactose epimerase deficiency	Definitive	AR

Mondo (3): galactose epimerase deficiency (MONDO:0009257), thrombocytopenia 13, syndromic (MONDO:0958333), 3-hydroxy-3-methylglutaric aciduria (MONDO:0009520)

Orphanet (3): Galactosemia (Orphanet:352), Galactose epimerase deficiency (Orphanet:79238), 3-hydroxy-3-methylglutaric aciduria (Orphanet:20)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000225	Gingival bleeding
HP:0000407	Sensorineural hearing impairment
HP:0000421	Epistaxis
HP:0000518	Cataract
HP:0000750	Delayed speech and language development
HP:0000952	Jaundice
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001342	Cerebral hemorrhage
HP:0001508	Failure to thrive
HP:0001634	Mitral valve prolapse
HP:0001704	Tricuspid valve prolapse
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001892	Abnormal bleeding
HP:0001902	Giant platelets
HP:0001903	Anemia
HP:0001923	Reticulocytosis
HP:0002013	Vomiting
HP:0002021	Pyloric stenosis
HP:0002194	Delayed gross motor development
HP:0002240	Hepatomegaly
HP:0003355	Aminoaciduria

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538324	3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5843 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 395,952 (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
CHEMBL1289	HALOPROGIN	4	8,799
CHEMBL411	DIETHYLSTILBESTROL	4	353,912
CHEMBL456	ETHACRYNIC ACID	4	20,004
CHEMBL51085	EBSELEN	3	13,237

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 6 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.85	IC50	14	nM	EBSELEN
6.30	IC50	500	nM	HALOPROGIN
5.44	IC50	3600	nM	PSAMMAPLIN A

PubChem BioAssay actives

3 with measured affinity, of 7 total; 3 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
2-phenyl-1,2-benzoselenazol-3-one	276473: Inhibition of human GalE by HPAEC assay	ic50	0.0140	uM
1,2,4-trichloro-5-(3-iodoprop-2-ynoxy)benzene	276473: Inhibition of human GalE by HPAEC assay	ic50	0.5000	uM
(2E)-3-(3-bromo-4-hydroxyphenyl)-N-[2-[2-[[(2E)-3-(3-bromo-4-hydroxyphenyl)-2-hydroxyiminopropanoyl]amino]ethyldisulfanyl]ethyl]-2-hydroxyiminopropanamide	276473: Inhibition of human GalE by HPAEC assay	ic50	3.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	10
sodium arsenite	decreases expression, increases abundance, increases expression	3
bisphenol A	decreases expression	2
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
thymidine 5’-diphosphate	affects binding	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
lariciresinol	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL911909	Binding	Inhibition of human GalE by HPAEC assay	Identification of novel inhibitors of UDP-Glc 4’-epimerase, a validated drug target for african sleeping sickness. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_VR11	HEK293T GALE KO clone 4	Transformed cell line	Female
CVCL_VR14	HEK293T GALE+GALK1 KO clone 12	Transformed cell line	Female
CVCL_VR15	HEK293T GALE+GALK2 KO clone 7	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan