Galactokinase deficiency

Summary

Galactokinase deficiency (MONDO:0009255) is a disease caused by GALK1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: GALK1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 533
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0012024	Hypergalactosemia	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0410061	Increased level of galactitol in plasma	Very frequent (80-99%)
HP:0410062	Increased level of galactitol in urine	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0100018	Nuclear cataract	Frequent (30-79%)
HP:0000815	Hypergonadotropic hypogonadism	Occasional (5-29%)
HP:0000842	Hyperinsulinemia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0008209	Premature ovarian insufficiency	Occasional (5-29%)
HP:0011098	Speech apraxia	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001508	Failure to thrive	Very rare (<1-4%)
HP:0001622	Premature birth	Very rare (<1-4%)
HP:0001943	Hypoglycemia	Very rare (<1-4%)
HP:0002361	Psychomotor deterioration	Very rare (<1-4%)
HP:0003124	Hypercholesterolemia	Very rare (<1-4%)
HP:0004431	Complement deficiency	Very rare (<1-4%)
HP:0011968	Feeding difficulties	Very rare (<1-4%)
HP:0012768	Neonatal asphyxia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	galactokinase deficiency
Mondo ID	MONDO:0009255
OMIM	230200
Orphanet	79237
DOID	DOID:14695
ICD-11	1173858031
NCIT	C114767
SNOMED CT	124302001
UMLS	C0268155
MedGen	120614
GARD	0002422
Is cancer (heuristic)	no

Also known as: galactokinase deficiency · galactokinase deficiency galactosemia · galactokinase deficiency with cataracts · galactosemia type 2 · GALK deficiency · GALK-D · hereditary galactokinase deficiency

Data availability: 533 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › galactosemia › galactokinase deficiency

Related subtypes (3): galactose epimerase deficiency, classic galactosemia, galactosemia 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

533 retrieved; paginated sample, class counts are floors:

281 likely benign, 93 uncertain significance, 60 likely pathogenic, 35 pathogenic, 28 pathogenic/likely pathogenic, 20 conflicting classifications of pathogenicity, 11 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069966	NM_000154.2(GALK1):c.510T>A (p.Cys170Ter)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076192	NM_000154.2(GALK1):c.67G>T (p.Glu23Ter)	GALK1	Pathogenic	criteria provided, single submitter
1368188	NM_000154.2(GALK1):c.1059del (p.Thr354fs)	GALK1	Pathogenic	criteria provided, single submitter
1371115	NM_000154.2(GALK1):c.162dup (p.Met55fs)	GALK1	Pathogenic	criteria provided, single submitter
1380137	NM_000154.2(GALK1):c.1107+1G>A	GALK1	Pathogenic	criteria provided, single submitter
1451771	NM_000154.2(GALK1):c.6del (p.Ala3fs)	GALK1	Pathogenic	criteria provided, single submitter
1452734	NM_000154.2(GALK1):c.265C>T (p.Gln89Ter)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456032	NM_000154.2(GALK1):c.768_769dup (p.Glu257fs)	GALK1	Pathogenic	criteria provided, single submitter
1457164	NC_000017.10:g.(?73754127)(73761239_?)del	GALK1	Pathogenic	criteria provided, single submitter
1458950	NM_000154.2(GALK1):c.364del (p.Leu122fs)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459536	NM_000154.2(GALK1):c.514C>T (p.Gln172Ter)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460428	NC_000017.10:g.(?73753076)(73754632_?)del	GALK1	Pathogenic	criteria provided, single submitter
1470566	NM_000154.2(GALK1):c.793+1G>T	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725988	NM_000154.2(GALK1):c.286C>T (p.Gln96Ter)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1897311	NM_000154.2(GALK1):c.793+2T>G	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1943313	NM_000154.2(GALK1):c.609dup (p.Arg204fs)	GALK1	Pathogenic	criteria provided, single submitter
2046151	NM_000154.2(GALK1):c.793+2T>C	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2110748	NM_000154.2(GALK1):c.837_841dup (p.Val281fs)	GALK1	Pathogenic	criteria provided, single submitter
2161092	NM_000154.2(GALK1):c.708C>A (p.Tyr236Ter)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422482	NC_000017.10:g.(?73759968)(73761239_?)del	GALK1	Pathogenic	criteria provided, single submitter
2422483	NC_000017.10:g.(?73758775)(73761239_?)del	GALK1	Pathogenic	criteria provided, single submitter
2422484	NC_000017.10:g.(?73754127)(73754690_?)del	GALK1	Pathogenic	criteria provided, single submitter
2675798	NM_000154.2(GALK1):c.901A>T (p.Arg301Ter)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2697749	NM_000154.2(GALK1):c.900_902del (p.Tyr300_Arg301delinsTer)	GALK1	Pathogenic	criteria provided, single submitter
2704911	NM_000154.2(GALK1):c.868C>T (p.Gln290Ter)	GALK1	Pathogenic	criteria provided, single submitter
2724583	NM_000154.2(GALK1):c.1A>G (p.Met1Val)	GALK1	Pathogenic	criteria provided, multiple submitters, no conflicts
2727681	NM_000154.2(GALK1):c.1055_1056del (p.Thr352fs)	GALK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736655	NM_000154.2(GALK1):c.416T>C (p.Leu139Pro)	GALK1	Pathogenic	criteria provided, single submitter
2760551	NM_000154.2(GALK1):c.953_954del (p.Asp317_Tyr318insTer)	GALK1	Pathogenic	criteria provided, single submitter
2768657	NM_000154.2(GALK1):c.83_84dup (p.Glu29fs)	GALK1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GALK1	Definitive	Autosomal recessive	galactokinase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GALK1	Orphanet:79237	Galactokinase deficiency
ITGB4	Orphanet:1114	Aplasia cutis congenita
ITGB4	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
ITGB4	Orphanet:251393	Localized junctional epidermolysis bullosa
ITGB4	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
ITGB4	Orphanet:79403	Junctional epidermolysis bullosa with pyloric atresia
NR3C1	Orphanet:786	Generalized glucocorticoid resistance syndrome
NR3C1	Orphanet:96253	Cushing disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GALK1	HGNC:4118	ENSG00000108479	P51570	Galactokinase	gencc,clinvar
ITGB4	HGNC:6158	ENSG00000132470	P16144	Integrin beta-4	clinvar
NR3C1	HGNC:7978	ENSG00000113580	P04150	Glucocorticoid receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GALK1	Galactokinase	Catalyzes the transfer of a phosphate from ATP to alpha-D-galactose and participates in the first committed step in the catabolism of galactose.
ITGB4	Integrin beta-4	Integrin alpha-6/beta-4 is a receptor for laminin.
NR3C1	Glucocorticoid receptor	Receptor for glucocorticoids (GC).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	128.6×	0.023
Antibody/Immunoglobulin	1	9.7×	0.104
Kinase	1	9.2×	0.104

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GALK1	Kinase	yes	2.7.1.6	Galactokinase, GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom
ITGB4	Antibody/Immunoglobulin	yes		EGF, Integrin_bsu_VWA, Calx_beta
NR3C1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Glcrtcd_rcpt, Znf_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
monocyte	1
right lobe of liver	1
minor salivary gland	1
skin of leg	1
tibial nerve	1
cartilage tissue	1
endothelial cell	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GALK1	174	ubiquitous	marker	right lobe of liver, apex of heart, monocyte
ITGB4	267	broad	marker	tibial nerve, minor salivary gland, skin of leg
NR3C1	302	ubiquitous	marker	endothelial cell, tibia, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR3C1	7,511
ITGB4	2,536
GALK1	2,244

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR3C1	P04150	58
GALK1	P51570	20
ITGB4	P16144	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GALK1 causes GALCT2	1	3806.7×	0.006	GALK1
Regulation of NPAS4 gene transcription	1	761.3×	0.010	NR3C1
PTK6 Expression	1	634.4×	0.010	NR3C1
Galactose catabolism	1	543.8×	0.010	GALK1
Type I hemidesmosome assembly	1	346.1×	0.013	ITGB4
Collagen formation	1	152.3×	0.019	ITGB4
Syndecan interactions	1	141.0×	0.019	ITGB4
Laminin interactions	1	126.9×	0.019	ITGB4
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	126.9×	0.019	NR3C1
SUMOylation of intracellular receptors	1	112.0×	0.020	NR3C1
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	92.8×	0.021	ITGB4
Developmental Cell Lineages	1	74.6×	0.021	ITGB4
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.021	ITGB4
Nuclear Receptor transcription pathway	1	66.8×	0.021	NR3C1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	64.5×	0.021	NR3C1
Cell junction organization	1	62.4×	0.021	ITGB4
Regulation of RUNX2 expression and activity	1	60.4×	0.021	NR3C1
Non-integrin membrane-ECM interactions	1	51.4×	0.024	ITGB4
Cell-Cell communication	1	45.9×	0.025	ITGB4
Potential therapeutics for SARS	1	38.1×	0.029	NR3C1
Extracellular matrix organization	1	21.0×	0.049	ITGB4
Developmental Biology	1	4.8×	0.194	ITGB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
galactitol metabolic process	1	5617.3×	0.002	GALK1
regulation of glucocorticoid biosynthetic process	1	5617.3×	0.002	NR3C1
glycolytic process from galactose	1	5617.3×	0.002	GALK1
response to wounding	2	147.8×	0.002	ITGB4, NR3C1
peripheral nervous system myelin formation	1	1872.4×	0.005	ITGB4
beta-D-galactose catabolic process via UDP-galactose, Leloir pathway	1	1123.5×	0.005	GALK1
glucocorticoid metabolic process	1	936.2×	0.005	NR3C1
hemidesmosome assembly	1	802.5×	0.005	ITGB4
nail development	1	802.5×	0.005	ITGB4
mammary gland duct morphogenesis	1	802.5×	0.005	NR3C1
trophoblast cell migration	1	802.5×	0.005	ITGB4
galactose metabolic process	1	702.2×	0.005	GALK1
nuclear receptor-mediated steroid hormone signaling pathway	1	702.2×	0.005	NR3C1
response to cortisol	1	561.7×	0.006	NR3C1
microglia differentiation	1	510.7×	0.006	NR3C1
mesodermal cell differentiation	1	510.7×	0.006	ITGB4
neuroinflammatory response	1	510.7×	0.006	NR3C1
skin morphogenesis	1	468.1×	0.006	ITGB4
regulation of gluconeogenesis	1	374.5×	0.007	NR3C1
maternal behavior	1	374.5×	0.007	NR3C1
cellular response to steroid hormone stimulus	1	351.1×	0.007	NR3C1
astrocyte differentiation	1	255.3×	0.009	NR3C1
adrenal gland development	1	224.7×	0.009	NR3C1
cell adhesion mediated by integrin	1	224.7×	0.009	ITGB4
filopodium assembly	1	216.1×	0.009	ITGB4
cellular response to glucocorticoid stimulus	1	208.1×	0.009	NR3C1
cellular response to dexamethasone stimulus	1	193.7×	0.010	NR3C1
motor behavior	1	187.2×	0.010	NR3C1
cell motility	1	133.8×	0.013	ITGB4
synaptic transmission, glutamatergic	1	119.5×	0.014	NR3C1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GALK1	PYRANTEL PAMOATE
NR3C1	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR3C1	162	4
GALK1	6	4
ITGB4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRANTEL PAMOATE	4	GALK1
HEXACHLOROPHENE	4	GALK1
CANDESARTAN CILEXETIL	4	NR3C1
DIENESTROL	4	NR3C1
PROGESTERONE	4	NR3C1
CLOTRIMAZOLE	4	NR3C1
SIMVASTATIN	4	NR3C1
ENZALUTAMIDE	4	NR3C1
EPLERENONE	4	NR3C1
CHLORMADINONE ACETATE	4	NR3C1
IDARUBICIN	4	NR3C1
CLOBETASOL PROPIONATE	4	NR3C1
MOMETASONE FUROATE	4	NR3C1
NORETHINDRONE	4	NR3C1
TESTOSTERONE PROPIONATE	4	NR3C1
PONATINIB	4	NR3C1
EXEMESTANE	4	NR3C1
BETAMETHASONE DIPROPIONATE	4	NR3C1
PREDNICARBATE	4	NR3C1
TIOCONAZOLE	4	NR3C1
BECLOMETHASONE DIPROPIONATE	4	NR3C1
DIFLORASONE DIACETATE	4	NR3C1
OXYMETHOLONE	4	NR3C1
DESOXYCORTICOSTERONE PIVALATE	4	NR3C1
FLUOROMETHOLONE	4	NR3C1
RIMEXOLONE	4	NR3C1
AMCINONIDE	4	NR3C1
HALCINONIDE	4	NR3C1
HYDROXYPROGESTERONE CAPROATE	4	NR3C1
LOTEPREDNOL ETABONATE	4	NR3C1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NR3C1	1,158	Binding:865, Functional:263, ADMET:28, Toxicity:2
GALK1	19	Binding:15, Functional:4
ITGB4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GALK1	2.7.1.6	galactokinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NR3C1	1,158

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PYRANTEL PAMOATE	4	GALK1
HEXACHLOROPHENE	4	GALK1
CANDESARTAN CILEXETIL	4	NR3C1
DIENESTROL	4	NR3C1
PROGESTERONE	4	NR3C1
CLOTRIMAZOLE	4	NR3C1
SIMVASTATIN	4	NR3C1
ENZALUTAMIDE	4	NR3C1
EPLERENONE	4	NR3C1
CHLORMADINONE ACETATE	4	NR3C1
IDARUBICIN	4	NR3C1
CLOBETASOL PROPIONATE	4	NR3C1
MOMETASONE FUROATE	4	NR3C1
NORETHINDRONE	4	NR3C1
TESTOSTERONE PROPIONATE	4	NR3C1
PONATINIB	4	NR3C1
EXEMESTANE	4	NR3C1
BETAMETHASONE DIPROPIONATE	4	NR3C1
PREDNICARBATE	4	NR3C1
TIOCONAZOLE	4	NR3C1
BECLOMETHASONE DIPROPIONATE	4	NR3C1
DIFLORASONE DIACETATE	4	NR3C1
OXYMETHOLONE	4	NR3C1
DESOXYCORTICOSTERONE PIVALATE	4	NR3C1
FLUOROMETHOLONE	4	NR3C1
RIMEXOLONE	4	NR3C1
AMCINONIDE	4	NR3C1
HALCINONIDE	4	NR3C1
HYDROXYPROGESTERONE CAPROATE	4	NR3C1
LOTEPREDNOL ETABONATE	4	NR3C1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	GALK1, NR3C1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ITGB4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ITGB4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns