TKFC

Summary

TKFC (triokinase and FMN cyclase, HGNC:24552) is a protein-coding gene on chromosome 11q12.2, encoding Triokinase/FMN cyclase (Q3LXA3). Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate.

This gene is a member of the family of dihydroxyacetone kinases, which have a protein structure distinct from other kinases. The product of this gene phosphorylates dihydroxyacetone, and also catalyzes the formation of riboflavin 4’,5’-phosphate (aka cyclin FMN) from FAD. Several alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 26007 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inborn error of immunity (Moderate, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 138 total — 2 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• MANE Select transcript: NM_015533

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24552
Approved symbol	TKFC
Name	triokinase and FMN cyclase
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP586B1621, NET45
Ensembl gene	ENSG00000149476
Ensembl biotype	protein_coding
OMIM	615844
Entrez	26007

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 21 protein_coding, 11 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000394900, ENST00000524440, ENST00000524953, ENST00000524968, ENST00000525170, ENST00000525366, ENST00000528061, ENST00000529092, ENST00000529121, ENST00000529479, ENST00000529620, ENST00000530057, ENST00000530329, ENST00000530456, ENST00000531820, ENST00000532173, ENST00000533393, ENST00000533853, ENST00000534084, ENST00000534134, ENST00000534370, ENST00000861183, ENST00000861184, ENST00000861185, ENST00000861186, ENST00000861187, ENST00000920730, ENST00000920731, ENST00000920732, ENST00000920733, ENST00000920734, ENST00000920735, ENST00000920736, ENST00000954339, ENST00000954340, ENST00000954341, ENST00000954342

RefSeq mRNA: 6 — MANE Select: NM_015533 NM_001351976, NM_001351977, NM_001351978, NM_001351979, NM_001351980, NM_015533

CCDS: CCDS8003

Canonical transcript exons

ENST00000394900 — 18 exons

Exon	Start	End
ENSE00000990788	61342755	61342844
ENSE00000990789	61343342	61343458
ENSE00001119045	61342461	61342495
ENSE00001144684	61343856	61343975
ENSE00001144706	61341823	61341912
ENSE00001197867	61346351	61349242
ENSE00001240470	61339066	61339176
ENSE00002274010	61341436	61341514
ENSE00002299385	61333228	61333329
ENSE00002460440	61345260	61345366
ENSE00003472953	61344136	61344273
ENSE00003506254	61342574	61342658
ENSE00003510054	61345462	61345565
ENSE00003572548	61345857	61345946
ENSE00003614598	61334620	61334731
ENSE00003636939	61337941	61338130
ENSE00003643541	61345712	61345745
ENSE00003786555	61339254	61339435

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.7510 / max 342.3235, expressed in 1809 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114553	16.8572	1806
114554	1.6236	873
114556	0.7043	34
114558	0.4035	161
114557	0.0555	35
114559	0.0333	12
114555	0.0275	11
114562	0.0212	10
114560	0.0160	4
114561	0.0090	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.04	gold quality
right adrenal gland	UBERON:0001233	98.99	gold quality
left adrenal gland cortex	UBERON:0035825	98.95	gold quality
left adrenal gland	UBERON:0001234	98.90	gold quality
right lobe of liver	UBERON:0001114	97.94	gold quality
right uterine tube	UBERON:0001302	97.92	gold quality
adrenal gland	UBERON:0002369	97.78	gold quality
adrenal cortex	UBERON:0001235	97.75	gold quality
right testis	UBERON:0004534	97.06	gold quality
left testis	UBERON:0004533	97.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.68	gold quality
small intestine	UBERON:0002108	95.59	gold quality
metanephros cortex	UBERON:0010533	95.21	gold quality
body of pancreas	UBERON:0001150	94.76	gold quality
duodenum	UBERON:0002114	94.55	gold quality
right lobe of thyroid gland	UBERON:0001119	94.42	gold quality
mucosa of transverse colon	UBERON:0004991	93.99	gold quality
left lobe of thyroid gland	UBERON:0001120	93.60	gold quality
skin of abdomen	UBERON:0001416	93.44	gold quality
testis	UBERON:0000473	93.32	gold quality
body of stomach	UBERON:0001161	93.28	gold quality
adenohypophysis	UBERON:0002196	93.03	gold quality
skin of leg	UBERON:0001511	92.75	gold quality
jejunal mucosa	UBERON:0000399	92.55	gold quality
adrenal tissue	UBERON:0018303	92.36	gold quality
thyroid gland	UBERON:0002046	92.24	gold quality
gall bladder	UBERON:0002110	91.99	gold quality
granulocyte	CL:0000094	91.98	gold quality
left ovary	UBERON:0002119	91.77	gold quality
transverse colon	UBERON:0001157	91.65	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	20.22
E-ANND-3	yes	10.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting TKFC, 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-4283	100.00	66.42	2097
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-516B-5P	99.56	66.33	1495

Literature-anchored findings (GeneRIF, showing 6)

• Evidence supports that a single protein sustains both FMN cyclase and ATP-dependent Dha kinase activities, probably in a single active center (PMID:16289032)
• DAK, the physiological suppressor of cytoplasmic viral RNA sensor MDA5, specifically inhibits MDA5- but not RNA helicase RIG-I-mediated innate antiviral signaling. (PMID:17600090)
• The peptide fragment (m/z 520.3) of DAK is a promising biomarker to guide timing of antiviral treatment and to avoid liver biopsy in compensated chronic hepatitis B patients. (PMID:24289155)
• analysis of human triokinase/FMN cyclase reveals that kinase activity requires intact homodimers, but cyclase requires only a truncated, single domain subunit (PMID:24569995)
• Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease. (PMID:32004446)
• Alternative Splicing of the Last TKFC Intron Yields Transcripts Differentially Expressed in Human Tissues That Code In Vitro for a Protein Devoid of Triokinase and FMN Cyclase Activity. (PMID:39456221)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tkfc	ENSDARG00000062085
mus_musculus	Tkfc	ENSMUSG00000034371
rattus_norvegicus	Tkfc	ENSRNOG00000020704
caenorhabditis_elegans		WBGENE00020962

Protein

Protein identifiers

Triokinase/FMN cyclase — Q3LXA3 (reviewed: Q3LXA3)

Alternative names: Bifunctional ATP-dependent dihydroxyacetone kinase/FAD-AMP lyase (cyclizing)

All UniProt accessions (6): Q3LXA3, A0A140VJH7, E9PJG8, E9PQR1, H0YCY6, I3L252

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate. Represses IFIH1-mediated cellular antiviral response.

Subunit / interactions. Homodimer. Interacts with IFIH1 (via the CARD domains), the interaction is inhibited by viral infection.

Tissue specificity. Detected in erythrocytes (at protein level).

Disease relevance. Triokinase and FMN cyclase deficiency syndrome (TKFCD) [MIM:618805] An autosomal recessive disease characterized by cataracts and developmental delay that may be associated with cerebellar hypoplasia. Additional features may include liver dysfunction, microcytic anemia, and fatal cardiomyopathy with lactic acidosis following a febrile illness. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Each activity is inhibited by the substrate(s) of the other.

Cofactor. Manganese or cobalt are requested for FAD-AMP lyase activity.

Domain organisation. DhaK and DhaL domains have differential roles, individually DhaK is inactive and DhaL displays cyclase but not kinase activity.

Miscellaneous. Inactive as DHA kinase and FMN cyclase.

Similarity. Belongs to the dihydroxyacetone kinase (DAK) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q3LXA3-1	1	yes
Q3LXA3-2	2

RefSeq proteins (6): NP_001338905, NP_001338906, NP_001338907, NP_001338908, NP_001338909, NP_056348* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004006	DhaK_dom	Domain
IPR004007	DhaL_dom	Domain
IPR012734	DhaK_ATP	Family
IPR036117	DhaL_dom_sf	Homologous_superfamily
IPR050861	Dihydroxyacetone_Kinase	Family

Pfam: PF02733, PF02734

Enzyme classification (BRENDA):

• EC 2.7.1.28 — triokinase (BRENDA: 4 organisms, 10 substrates, 4 inhibitors, 31 Km, 20 kcat entries)
• EC 2.7.1.29 — glycerone kinase (BRENDA: 23 organisms, 37 substrates, 17 inhibitors, 21 Km, 9 kcat entries)
• EC 4.6.1.15 — FAD-AMP lyase (cyclizing) (BRENDA: 2 organisms, 1 substrates, 8 inhibitors, 4 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0057–0.24	16
D-GLYCERALDEHYDE	0.0071–0.019	8
DIHYDROXYACETONE	0.0012–2.2	8
ATP	0.0003–0.63	7
DIHYDROXYACETONE	0.006–0.0663	6
GLYCERONE PHOSPHATE	0.005–0.006	2
FAD	0.009–0.09	2
GLYCERALDEHYDE	0.01	1
1,3-DIHYDROXY-2-PROPANONE	0.022	1
D,L-GLYCERALDEHYDE	0.18	1
DL-GLYCERALDEHYDE	0.024	1

Catalyzed reactions (Rhea), 3 shown:

• FAD = riboflavin cyclic-4’,5’-phosphate + AMP + H(+) (RHEA:13729)
• D-glyceraldehyde + ATP = D-glyceraldehyde 3-phosphate + ADP + H(+) (RHEA:13941)
• dihydroxyacetone + ATP = dihydroxyacetone phosphate + ADP + H(+) (RHEA:15773)

UniProt features (34 total): binding site 8, mutagenesis site 8, sequence conflict 5, sequence variant 4, modified residue 3, domain 2, chain 1, splice variant 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3LXA3-F1	95.40	0.91

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): 221 (tele-hemiaminal-histidine intermediate)

Ligand- & substrate-binding residues (8): 486; 494–495; 556–558; 56–59; 109; 114; 401–404; 446–447

Post-translational modifications (3): 350, 511, 545

Mutagenesis-validated functional residues (8):

Position	Phenotype
112	highly decreases kinase activity. no effect on fmn cyclase activity.
204	slightly decreases kinase activity. no effect on fmn cyclase activity.
221	abolishes kinase activity but not fmn cyclase activity.
401	abolishes both kinase and fmn cyclase activities.
403	abolishes both kinase and fmn cyclase activities.
404	decreases both kinase and fmn cyclase activities.
446	decreases both kinase and fmn cyclase activities.
556	abolishes both kinase and fmn cyclase activities.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-70350	Fructose catabolism
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses

MSigDB gene sets: 216 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, RNGTGGGC_UNKNOWN, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_GSTM1, GNF2_HPN, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POLYOL_CATABOLIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_PHOSPHORYLATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, COUP_01, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (7): carbohydrate metabolic process (GO:0005975), glycerol catabolic process (GO:0019563), negative regulation of MDA-5 signaling pathway (GO:0039534), regulation of innate immune response (GO:0045088), carbohydrate phosphorylation (GO:0046835), obsolete fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate (GO:0061624), glycerol metabolic process (GO:0006071)

GO Molecular Function (12): glycerone kinase activity (GO:0004371), ATP binding (GO:0005524), FAD-AMP lyase (cyclizing) activity (GO:0034012), metal ion binding (GO:0046872), triokinase activity (GO:0050354), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, alcohol group as acceptor (GO:0016773), lyase activity (GO:0016829)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
Fructose metabolism	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carbohydrate metabolic process	2
kinase activity	2
phosphotransferase activity, alcohol group as acceptor	2
transferase activity, transferring phosphorus-containing groups	2
catalytic activity	2
primary metabolic process	1
glycerol metabolic process	1
alditol catabolic process	1
MDA-5 signaling pathway	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
regulation of MDA-5 signaling pathway	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
innate immune response	1
regulation of immune response	1
phosphorylation	1
polyol metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cyclase activity	1
phosphorus-oxygen lyase activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1436 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TKFC	GLYCTK	Q8IVS8	966
TKFC	KHK	P50053	708
TKFC	SYP	P08247	578
TKFC	CHGA	P10645	573
TKFC	ESD	P10768	566
TKFC	GK	P32189	549
TKFC	TPI1	P00938	546
TKFC	ALDOB	P05062	538
TKFC	IFIH1	Q9BYX4	538
TKFC	GK2	Q14410	536
TKFC	SLC2A5	P22732	519
TKFC	NLRX1	Q86UT6	503
TKFC	RNF125	Q96EQ8	469
TKFC	GPD2	P43304	422
TKFC	RBBP9	O75884	421

IntAct

63 interactions, top by confidence:

A	B	Type	Score
NME3	NME4	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
IFIH1	TKFC	psi-mi:“MI:0915”(physical association)	0.620
IFIH1	TKFC	psi-mi:“MI:0914”(association)	0.620
SDCBP	TKFC	psi-mi:“MI:0915”(physical association)	0.560
TKFC	SDCBP	psi-mi:“MI:0915”(physical association)	0.560
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
RDH12	NME2P1	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
WASHC3	WASH3P	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
IFIH1	IKBKE	psi-mi:“MI:0914”(association)	0.500
RP2	QSOX1	psi-mi:“MI:0914”(association)	0.350
IQCF1	TBC1D4	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
RAB11A	SCAMP1	psi-mi:“MI:0914”(association)	0.350
RAB2A	TOMM40	psi-mi:“MI:0914”(association)	0.350
GYPA	HYKK	psi-mi:“MI:0914”(association)	0.350
CENPM	DNM1L	psi-mi:“MI:0914”(association)	0.350
IFT20	EXOC5	psi-mi:“MI:0914”(association)	0.350
C3orf18	EXOC5	psi-mi:“MI:0914”(association)	0.350

BioGRID (107): DAK (Two-hybrid), DAK (Affinity Capture-RNA), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS), DAK (Co-fractionation), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS), DAK (Reconstituted Complex), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS), DAK (Affinity Capture-MS)

ESM2 similar proteins: A2XNR6, A5A6P1, A5GFY8, B0X4N8, D4AAT7, O04130, O08651, O43175, O49485, O65361, P13803, P13804, P32232, P35520, P37142, P40939, P49079, P49080, P54887, P54888, Q16T79, Q29554, Q2QS13, Q3LXA3, Q42806, Q42942, Q4KLZ6, Q59A32, Q5EAD2, Q5R7M2, Q5RC31, Q60HD7, Q61753, Q64428, Q64737, Q67U69, Q75LJ3, Q8AWD2, Q91Z53, Q941T1

Diamond homologs: A0QXE4, A0R758, F1RKQ4, O04059, P43550, P45510, P76014, P76015, Q3LXA3, Q4KLZ6, Q58DK4, Q6D8V6, Q8VC30, Q927E5, Q927E6, Q92EU2, Q92EU3, Q9CIV8, Q9CIW0, P45620, Q9CIV7, O13902, O49227, O60017, O74192, O74215, P54838, Q55EE0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TKFC	“down-regulates quantity”	D-glyceraldehyde	“chemical modification”
TKFC	“down-regulates quantity”	“D-glyceraldehyde 3-phosphate(2-)”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	102
Likely benign	8
Benign	8

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
816699	NM_015533.4(TKFC):c.1628G>T (p.Arg543Ile)	Likely pathogenic
816700	NM_015533.4(TKFC):c.1333G>A (p.Gly445Ser)	Likely pathogenic

SpliceAI

3122 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61333277:G:GT	donor_gain	1.0000
11:61333277:G:T	donor_gain	1.0000
11:61333327:G:GT	donor_gain	1.0000
11:61333327:G:T	donor_gain	1.0000
11:61337936:T:TA	acceptor_gain	1.0000
11:61337937:GCA:G	acceptor_loss	1.0000
11:61337939:A:AG	acceptor_gain	1.0000
11:61337940:G:GA	acceptor_gain	1.0000
11:61337940:GA:G	acceptor_gain	1.0000
11:61337940:GAC:G	acceptor_gain	1.0000
11:61337940:GACC:G	acceptor_gain	1.0000
11:61337940:GACCT:G	acceptor_gain	1.0000
11:61338126:TGCTG:T	donor_gain	1.0000
11:61338127:GCTG:G	donor_gain	1.0000
11:61338127:GCTGG:G	donor_gain	1.0000
11:61338128:CTG:C	donor_gain	1.0000
11:61338129:TG:T	donor_gain	1.0000
11:61338130:GG:G	donor_gain	1.0000
11:61338131:G:C	donor_loss	1.0000
11:61338131:G:GG	donor_gain	1.0000
11:61338132:T:A	donor_loss	1.0000
11:61339061:TCCA:T	acceptor_loss	1.0000
11:61339064:A:AG	acceptor_gain	1.0000
11:61339064:AG:A	acceptor_gain	1.0000
11:61339065:G:GG	acceptor_gain	1.0000
11:61339065:GG:G	acceptor_gain	1.0000
11:61339065:GGT:G	acceptor_gain	1.0000
11:61339065:GGTT:G	acceptor_gain	1.0000
11:61339177:G:GA	donor_loss	1.0000
11:61339178:T:A	donor_loss	1.0000

AlphaMissense

3650 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61339113:T:C	F81L	0.999
11:61339115:C:A	F81L	0.999
11:61339115:C:G	F81L	0.999
11:61339367:G:C	D140H	0.997
11:61339113:T:A	F81I	0.996
11:61339290:A:C	D114A	0.996
11:61339290:A:T	D114V	0.996
11:61339301:T:C	F118L	0.996
11:61339303:C:A	F118L	0.996
11:61339303:C:G	F118L	0.996
11:61339368:A:T	D140V	0.996
11:61339435:G:C	K162N	0.996
11:61339435:G:T	K162N	0.996
11:61344220:A:C	D396A	0.996
11:61344235:A:T	D401V	0.996
11:61338110:G:A	G58D	0.995
11:61342466:C:G	H221D	0.995
11:61342780:C:A	N267K	0.995
11:61342780:C:G	N267K	0.995
11:61344220:A:T	D396V	0.995
11:61339113:T:G	F81V	0.994
11:61339289:G:C	D114H	0.994
11:61339290:A:G	D114G	0.994
11:61339368:A:C	D140A	0.994
11:61341837:A:C	S194R	0.994
11:61341839:C:A	S194R	0.994
11:61341839:C:G	S194R	0.994
11:61342473:A:T	E223V	0.994
11:61344236:C:A	D401E	0.994
11:61344236:C:G	D401E	0.994

dbSNP variants (sampled 300 via entrez): RS1000059022 (11:61335536 G>T), RS1000205947 (11:61342357 C>T), RS1000367641 (11:61335813 A>T), RS1000683231 (11:61334253 C>G), RS1001022368 (11:61351520 A>C,G), RS1001285657 (11:61341277 G>C), RS1001596818 (11:61353505 C>T), RS1001826323 (11:61346964 C>T), RS1001835763 (11:61352342 T>C), RS1001846519 (11:61351741 T>C), RS1001855798 (11:61335607 T>C), RS1001930716 (11:61352031 G>A), RS1001962576 (11:61352051 G>A), RS1002154556 (11:61339673 C>G,T), RS1002456917 (11:61334108 A>G)

Disease associations

OMIM: gene MIM:615844 | disease phenotypes: MIM:618805, MIM:212350

GenCC curated gene-disease

Disease	Classification	Inheritance
inborn error of immunity	Moderate	Autosomal recessive
Sengers syndrome	Supportive	Autosomal recessive
triokinase and FMN cyclase deficiency syndrome	Limited	Autosomal recessive

Mondo (4): triokinase and FMN cyclase deficiency syndrome (MONDO:0032927), Sengers syndrome (MONDO:0008922), inborn errors of metabolism (MONDO:0019052), inborn error of immunity (MONDO:0003778)

Orphanet (2): Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome (Orphanet:1369), Rare inborn errors of metabolism (Orphanet:68367)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000545	Myopia
HP:0000568	Microphthalmia
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0001131	Corneal dystrophy
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001321	Cerebellar hypoplasia
HP:0001397	Hepatic steatosis
HP:0001531	Failure to thrive in infancy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001733	Pancreatitis
HP:0001935	Microcytic anemia
HP:0002028	Chronic diarrhea
HP:0002136	Broad-based gait
HP:0002188	Delayed CNS myelination
HP:0002240	Hepatomegaly
HP:0003073	Hypoalbuminemia
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0006673	Reduced systolic function
HP:0031964	Elevated circulating alanine aminotransferase concentration

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007153	Immunologic Deficiency Syndromes	C20.673
D008661	Metabolism, Inborn Errors	C16.320.565; C18.452.648
C538280	Cataract and cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067305 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
sodium arsenite	affects cotreatment, increases abundance, decreases expression	3
Valproic Acid	affects cotreatment, decreases expression	3
sodium arsenate	decreases expression, increases abundance	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Arsenic	decreases expression, increases abundance, affects cotreatment	2
Smoke	decreases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
bufotalin	decreases expression	1
methylmercuric chloride	decreases expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
periodate-oxidized adenosine	affects expression	1
ferrous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
nivalenol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases 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
CHEMBL5651233	Binding	Binding affinity to human DAK incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00468273	PHASE3	COMPLETED	A Clinical Study of Intravenous Immunoglobulin
NCT00811174	PHASE3	TERMINATED	Efficacy, Safety and Kinetics Study of Octagam 10% in Primary Immunodeficiency Diseases
NCT01012323	PHASE3	COMPLETED	A Study of NewGam, Human Immunoglobulin 10%, in Patients With Primary Immunodeficiency Diseases
NCT01313507	PHASE3	COMPLETED	High Infusion Rate Study of Immunoglobulin Intravenous (Human) 10% (NewGam)
NCT01406470	PHASE3	COMPLETED	Phase 3 Study of Immune Globulin Intravenous (Human)IVIG-SN™ in Subjects With Primary Immunodeficiency
NCT02783482	PHASE3	COMPLETED	Study of Immune Globulin Intravenous (Human) GC5107 in Subjects With Primary Humoral Immunodeficiency
NCT02810444	PHASE3	COMPLETED	Study to Investigate Efficacy, Safety and Pharmacokinetics of BT595 in Subjects With PID
NCT03961009	PHASE3	COMPLETED	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients
NCT04842643	PHASE3	COMPLETED	An Extension Study of TAK-664 for Japanese People With Primary Immunodeficiency Disease
NCT04944979	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
NCT06089122	PHASE3	UNKNOWN	Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG
NCT06150833	PHASE3	UNKNOWN	Efficacy and Safety and Pharmacokinetics of Boya IVIG
NCT07346859	PHASE3	RECRUITING	Study of BP-SCIG 20% in Patients With Primary Immunodeficiency (PID)
NCT00654433	PHASE3	TERMINATED	ALD-101 Adjuvant Therapy of Unrelated Umbilical Cord Blood Transfusion (UCBT) in Patients With Inherited Metabolic Diseases
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00389324	PHASE2	COMPLETED	A Trial of the Pharmacokinetics, Safety, and Tolerability of Subcutaneous Gamunex® in Primary Immunodeficiency
NCT00598481	PHASE2	COMPLETED	ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID
NCT01856582	PHASE2	TERMINATED	CD34+ Stem Cell Infusion to Augment Graft Function
NCT06199427	PHASE2	RECRUITING	PTCy and and Ruxolitinib for GVHD Prophylaxis After HSCT With Thymoglobulin in Conditioning Regimen in Patients With Inborn Errors of Immunity
NCT00001596	PHASE2	COMPLETED	Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
NCT01049854	PHASE2	COMPLETED	CD34+Selection for Partially Matched Family or Matched Unrelated Adult Donor Transplant
NCT01341379	PHASE2	WITHDRAWN	Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT02349906	PHASE2	COMPLETED	Treosulfan-based Versus Busulfan-based Conditioning in Paediatric Patients With Non-malignant Diseases
NCT03367546	PHASE2	TERMINATED	Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation (HaploHCT) Following Reduced Intensity Conditioning (RIC) for Selected High Risk Non-Malignant Diseases
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04644016	PHASE2	RECRUITING	Cord Blood Transplant in Children and Young Adults With Blood Cancers and Non-malignant Disorders
NCT00692926	PHASE1	COMPLETED	Unrelated Umbilical Cord Blood Transplantation Augmented With ALDHbr Umbilical Cord Blood Cells
NCT00744692	PHASE1	COMPLETED	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant in Pediatric Patients With Non-Malignant Disorders
NCT01003912	PHASE1	WITHDRAWN	Fetal Umbilical Cord Blood (UCB) Transplant for Lysosomal Storage Diseases
NCT00001158	Not specified	COMPLETED	Studies of the Immune Response in Normal Subjects and Patients With Disorders of the Immune System
NCT00001336	Not specified	COMPLETED	In Vitro Studies of Immunological and Stem Cell Function in Peripheral Blood Mononuclear Cells in Patients
NCT00001788	Not specified	TERMINATED	Genetic Basis of Primary Immunodeficiencies
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006131	Not specified	COMPLETED	Randomized Study of Two Doses of Oral Valacyclovir in Immunocompromised Patients With Uncomplicated Herpes Zoster
NCT01150240	Not specified	UNKNOWN	Clinical and Laboratory Online Patient- and Research Database for Primary Immunodeficiencies in Switzerland