FCSK

protein-coding

fucose kinase

Gene summary

The protein encoded by this gene belongs to the GHMP (galacto-, homoserine, mevalonate and phosphomevalonate) kinase family and catalyzes the phosphorylation of L-fucose to form beta-L-fucose 1-phosphate. This enzyme catalyzes the first step in the utilization of free L-fucose in glycoprotein and glycolipid synthesis. L-fucose may be important in mediating a number of cell-cell interactions such as blood group antigen recognition, inflammation, and metastatis. While several transcript variants may exist for this gene, the full-length nature of only one has been described to date. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_145059.3

Inheritance

ClinVar variants

P:11U:409B:181

Top phenotype

Congenital disorder of glycosylation with defective fucosylation 2

gnomAD constraint

pLI —, LoF o/e 0.89

Max pathogenic AF

—

Genomic locus

chr16:70,454,595-70,480,274

External References & Databases

Ensembl (ENSG00000157353)

Transcript & Mutation Effects

hg38 • Region Span ~25.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital disorder of glycosylation with defective fucosylation 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0020777

Submitter: Ambry Genetics

congenital disorder of glycosylation with defective fucosylation 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020777

Submitter: PanelApp Australia

congenital disorder of glycosylation with defective fucosylation 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0020777

Submitter: ClinGen

FCSK was first reported in relation to autosomal recessive congenital disorder of glycosylation with defective fucosylation 2 in 2018 (Ng et al., PMID: 30503518). Six unique variants (missense and frameshift) that have been reported in five probands in four publications are included in this curation. This gene-disease relationship is also supported by the biochemical function of FCSK, which is a fucokinase that functions in the salvage pathway to generate GDP-fucose. Both a proband and a CRISPR/Cas9-based cell line knockout model exhibited defects in fucokinase activity (Ng et al., PMID: 30503518). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date September 18, 2024 (SOP Version 10).

congenital disorder of glycosylation with defective fucosylation 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020777

Submitter: G2P

congenital disorder of glycosylation with defective fucosylation 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0020777

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation with defective fucosylation 2AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 30503518

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FCSK variants in ClinVar

5 Conditions Cataloged

not providedTotal: 503

not specifiedTotal: 284

FCSK-related disorderTotal: 55

Congenital disorder of glycosylation with defective fucosylation 2Total: 40

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145059.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	126 clinvar	12 clinvar	140
missense		1 clinvar	369 clinvar	34 clinvar	8 clinvar	412
nonsense		2 clinvar	15 clinvar			17
start loss						0
frameshift		5 clinvar	9 clinvar			14
splice donor/acceptor (+/-2bp)		3 clinvar	14 clinvar	1 clinvar		18
Total	0	11	409	161	20	601

Highest pathogenic variant AF is 0.00020477244

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145059.3	RefSeq	NP_659496.2	23	MANE Select
ENST00000288078.11	Ensembl	ENSP00000288078.6	23	MANE Select
ENST00000378912.6	Ensembl	ENSP00000368192.2	23	Standard
ENST00000378912.7	Ensembl	ENSP00000368192.2	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fructose and mannose metabolism - Homo sapiens (human)
Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
Fructose intolerance, hereditary
Fructose and Mannose Degradation
Fructosuria

Biological Process

GDP-L-fucose salvage
carbohydrate phosphorylation
response to dopamine

Molecular Function

ATP binding
fucokinase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000288078
Coding exons: 23
Length: 25854
Individuals with no LoFs: 124543
Homozygous LoFs: 0
Heterozygous LoFs: 263
Defined: 124806
p: 0.00105

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.396	634	663	0.957	0.0000427	6783
Missense (PolyPhen)		165	198.22	0.8324		2102
Synonymous	0.155	287	290	0.988	0.0000189	2346
Loss of Function	0.750	48	53.9	0.890	0.00000284	552

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0018	0.0017	notable
Latino/Admixed American	0.0022	0.0020	notable
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.0015	0.0014	notable
Finnish	0.00010	0.000093	rare
European (Non-Finnish)	0.0010	0.00094	notable
South Asian	0.00070	0.00069	rare
Other	0.0014	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Takes part in the salvage pathway for reutilization of fucose from the degradation of oligosaccharides.;

Recessive Scores

pRec: 0.137

Intolerance Scores

LoFtool: 0.427
RVIS EVS: -0.92
RVIS percentile EVS: 9.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.954

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium