Galactosemia 4

Summary

Galactosemia 4 (MONDO:0030105) is a disease caused by GALM (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: GALM (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Validated
Annual incidence	1-9 / 100 000	1.2	Japan	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0004915	Impairment of galactose metabolism	Very frequent (80-99%)
HP:0012024	Hypergalactosemia	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0001396	Cholestasis	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Very rare (<1-4%)
HP:0001508	Failure to thrive	Very rare (<1-4%)
HP:0002240	Hepatomegaly	Very rare (<1-4%)
HP:0100806	Sepsis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	galactosemia 4
Mondo ID	MONDO:0030105
OMIM	618881
Orphanet	570422
DOID	DOID:0060969
UMLS	C5394377
MedGen	1718159
GARD	0018005
Is cancer (heuristic)	no

Also known as: GALAC4 · Galactose Mutarotase Deficiency · GALACTOSEMIA IV · galactosemia iv · GALM mutarotase deficiency

Data availability: 9 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › galactosemia › galactosemia 4

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

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

9 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 uncertain significance, 1 benign, 1 likely benign, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
873020	NM_138801.3(GALM):c.294del (p.Ile99fs)	GALM	Pathogenic	no assertion criteria provided
873021	NM_138801.3(GALM):c.244C>T (p.Arg82Ter)	GALM	Pathogenic	criteria provided, single submitter
873024	NM_138801.3(GALM):c.932G>A (p.Trp311Ter)	GALM	Pathogenic	no assertion criteria provided
4845671	NM_138801.3(GALM):c.457del (p.Asp153fs)	GALM	Likely pathogenic	criteria provided, single submitter
873023	NM_138801.3(GALM):c.424G>A (p.Gly142Arg)	GALM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1687267	NM_138801.3(GALM):c.661_663del (p.Ala221del)	GALM	Uncertain significance	criteria provided, single submitter
873022	NM_138801.3(GALM):c.799C>G (p.Arg267Gly)	GALM	Uncertain significance	criteria provided, single submitter
1222775	NM_138801.3(GALM):c.568A>T (p.Asn190Tyr)	GALM	Benign	criteria provided, multiple submitters, no conflicts
4795867	NM_138801.3(GALM):c.955C>T (p.Arg319Cys)	GALM	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
GALM	Strong	Autosomal recessive	galactosemia 4	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GALM	Orphanet:570422	Galactose mutarotase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GALM	HGNC:24063	ENSG00000143891	Q96C23	Galactose mutarotase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GALM	Galactose mutarotase	Mutarotase that catalyzes the interconversion of beta-D-galactose and alpha-D-galactose during galactose metabolism.

Protein-family classification

Druggable: 1 · 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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GALM	Enzyme (other)	yes	5.1.3.3	Aldose_1/G6P_1-epimerase, Gal_mutarotase_sf_dom, GH-type_carb-bd

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
kidney epithelium	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GALM	257	ubiquitous	marker	kidney epithelium, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GALM	1,631

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GALM	Q96C23	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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 GALM causes GALAC4	1	11420.0×	2e-04	GALM
Galactose catabolism	1	1631.4×	6e-04	GALM

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
beta-D-galactose catabolic process via UDP-galactose, Leloir pathway	1	3370.4×	9e-04	GALM
galactose metabolic process	1	2106.5×	9e-04	GALM
glucose metabolic process	1	255.3×	0.005	GALM
carbohydrate metabolic process	1	135.9×	0.007	GALM

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
GALM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GALM	5.1.3.3	Aldose 1-epimerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	GALM
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)
GALM	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.