Classic galactosemia

Summary

Classic galactosemia (MONDO:0009258) is a disease caused by GALT (GenCC Definitive), with 2 cohort genes and 5 clinical trials. Top therapeutic interventions include govorestat and arginine aspartate.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: GALT (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 753
• Phenotypes (HPO): 54
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.1	Europe	Validated
Prevalence at birth	1-9 / 100 000	3	Netherlands	Validated
Prevalence at birth	1-9 / 100 000	2.3	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	4.3	Ireland	Validated
Prevalence at birth	1-9 / 1 000 000	0.13	Japan	Validated
Prevalence at birth	1-9 / 1 000 000	0.25	China	Validated
Prevalence at birth	1-5 / 10 000	20.8	Iran, Islamic Republic of	Validated

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000707	Abnormality of the nervous system	Very frequent (80-99%)
HP:0003251	Male infertility	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0030272	Abnormal erythrocyte enzyme activity	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000786	Primary amenorrhea	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000868	Decreased fertility in females	Frequent (30-79%)
HP:0000869	Secondary amenorrhea	Frequent (30-79%)
HP:0000876	Oligomenorrhea	Frequent (30-79%)
HP:0000952	Jaundice	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001399	Hepatic failure	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002174	Postural tremor	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002345	Action tremor	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0006977	Grammar-specific speech disorder	Frequent (30-79%)
HP:0008209	Premature ovarian insufficiency	Frequent (30-79%)
HP:0009088	Speech articulation difficulties	Frequent (30-79%)
HP:0012537	Food intolerance	Frequent (30-79%)
HP:0030353	Decreased serum insulin-like growth factor 1	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002141	Gait imbalance	Occasional (5-29%)
HP:0002311	Incoordination	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0004349	Reduced bone mineral density	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0011098	Speech apraxia	Occasional (5-29%)
HP:0011446	Abnormality of higher mental function	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	classic galactosemia
Mondo ID	MONDO:0009258
OMIM	230400
Orphanet	79239
DOID	DOID:0111459
ICD-11	2011000259
SNOMED CT	10899004
UMLS	C0268151
MedGen	82777
GARD	0013639
Is cancer (heuristic)	no

Also known as: classic galactosemia · classical galactosemia, homozygous duarte-type · galactose-1-phosphate uridyltransferase deficiency · galactosemia type 1 · GALT deficiency · transferase deficiency

Data availability: 753 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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

Related subtypes (3): galactokinase deficiency, galactose epimerase deficiency, 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

600 retrieved; paginated sample, class counts are floors:

241 likely benign, 78 pathogenic/likely pathogenic, 77 pathogenic, 69 uncertain significance, 67 likely pathogenic, 57 conflicting classifications of pathogenicity, 4 benign, 4 benign/likely benign, 2 conflicting classifications of pathogenicity; other, 1 benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1705146	NM_000155.4(GALT):c.[413C>T;469G>A]		Pathogenic	criteria provided, single submitter
242644	NM_000155.2(GALT):c.[-1039_753del;820+50_*789delinsGAATAGACCCCA]		Pathogenic	no assertion criteria provided
101049	NC_000009.11:g.(34644527_34645701)_(34650746_34653247)del	GALT	Pathogenic	no assertion criteria provided
1066673	NM_000155.4(GALT):c.428C>G (p.Ser143Trp)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067186	NM_000155.4(GALT):c.508-2_509del	GALT	Pathogenic	criteria provided, single submitter
1073718	NM_000155.4(GALT):c.814del (p.Arg272fs)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299297	NC000009.12:g.(34646588_34655077)del	GALT	Pathogenic	criteria provided, single submitter
1324452	NM_000155.4(GALT):c.957C>G (p.His319Gln)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332994	NM_000155.4(GALT):c.467C>A (p.Ser156Ter)	GALT	Pathogenic	no assertion criteria provided
1332995	NM_000155.4(GALT):c.200del (p.Arg67fs)	GALT	Pathogenic	criteria provided, multiple submitters, no conflicts
1332996	NM_000155.4(GALT):c.708_709del (p.Ser236fs)	GALT	Pathogenic	no assertion criteria provided
1355405	NM_000155.4(GALT):c.40_41insT (p.Ala14fs)	GALT	Pathogenic	criteria provided, single submitter
1360292	NM_000155.4(GALT):c.684del (p.Lys229fs)	GALT	Pathogenic	criteria provided, single submitter
1378874	NM_000155.4(GALT):c.576_589del (p.Ser192fs)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426580	NM_000155.4(GALT):c.530T>C (p.Met177Thr)	GALT	Pathogenic	criteria provided, single submitter
1451313	NM_000155.4(GALT):c.327del (p.Gly110fs)	GALT	Pathogenic	criteria provided, single submitter
1454503	NM_000155.4(GALT):c.384_388del (p.Met129fs)	GALT	Pathogenic	criteria provided, single submitter
1457073	NM_000155.4(GALT):c.558C>G (p.His186Gln)	GALT	Pathogenic	criteria provided, single submitter
1457165	NC_000009.11:g.(?34646573)(34650446_?)del	GALT	Pathogenic	criteria provided, single submitter
1457166	NC_000009.11:g.(?34646579)(34655067_?)del	GALT	Pathogenic	criteria provided, single submitter
1457366	NM_000155.4(GALT):c.462G>A (p.Trp154Ter)	GALT	Pathogenic	criteria provided, multiple submitters, no conflicts
1458107	NM_000155.4(GALT):c.894G>A (p.Met298Ile)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458954	NM_000155.4(GALT):c.425T>C (p.Met142Thr)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1470556	NM_000155.4(GALT):c.152G>T (p.Arg51Leu)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1482501	NM_000155.4(GALT):c.667C>A (p.Arg223Ser)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167128	NM_000155.4(GALT):c.445dup (p.Ala149fs)	GALT	Pathogenic	criteria provided, multiple submitters, no conflicts
1684618	NM_000155.4(GALT):c.772del (p.Arg258fs)	GALT	Pathogenic	no assertion criteria provided
1685839	NM_000155.4(GALT):c.142C>A (p.Arg48Ser)	GALT	Pathogenic	criteria provided, single submitter
1687586	NM_000155.4(GALT):c.328+2T>C	GALT	Pathogenic	criteria provided, single submitter
1691431	NM_000155.4(GALT):c.1001A>G (p.Lys334Arg)	GALT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
GALT	Definitive	Autosomal recessive	galactosemia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GALT	Orphanet:79239	Classic galactosemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GALT	HGNC:4135	ENSG00000213930	P07902	Galactose-1-phosphate uridylyltransferase	gencc,clinvar
FAM219A	HGNC:19920	ENSG00000164970	Q8IW50	Protein FAM219A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GALT	Galactose-1-phosphate uridylyltransferase	Plays an important role in galactose metabolism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GALT	Enzyme (other)	yes	2.7.7.12	GalP_UDPtransf1, GalP_Utransf_N, GalP_Utransf_C
FAM219A	Other/Unknown	no		FAM219

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right adrenal gland	1
right lobe of liver	1
medulla oblongata	1
superior vestibular nucleus	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GALT	225	ubiquitous	marker	right lobe of liver, right adrenal gland, apex of heart
FAM219A	245	ubiquitous	yes	ventricular zone, superior vestibular nucleus, medulla oblongata

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GALT	708
FAM219A	411

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GALT	P07902	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAM219A	Q8IW50	63.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GALT can cause GALCT	1	11420.0×	2e-04	GALT
Galactose catabolism	1	1631.4×	6e-04	GALT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
UDP-alpha-D-glucose metabolic process	1	5617.3×	4e-04	GALT
beta-D-galactose catabolic process via UDP-galactose, Leloir pathway	1	3370.4×	4e-04	GALT
galactose metabolic process	1	2106.5×	5e-04	GALT

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GALT	0	0
FAM219A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GALT	2.7.7.12	UDP-glucose-hexose-1-phosphate uridylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GALT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FAM219A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GALT	0	—
FAM219A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1
PHASE3	1
PHASE2	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04902781	PHASE2/PHASE3	COMPLETED	Clinical Benefit, Safety, PK and PD Study of AT-007 in Pediatric Subjects With Classic Galactosemia
NCT05418829	PHASE3	UNKNOWN	AT-007 in Adult Subjects With Classic Galactosemia (CG)
NCT03580122	PHASE2	COMPLETED	The Effect of Arginine on Classic Galactosemia
NCT04117711	PHASE1/PHASE2	COMPLETED	Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia
NCT03838016	EARLY_PHASE1	COMPLETED	Preventing Speech and Language Disorders in Children With Classic Galactosemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GOVORESTAT	3	3
ARGININE ASPARTATE	2	1