FTCD

Summary

FTCD (formimidoyltransferase cyclodeaminase, HGNC:3974) is a protein-coding gene on chromosome 21q22.3, encoding Formimidoyltransferase-cyclodeaminase (O95954). Folate-dependent enzyme, that displays both transferase and deaminase activity.

The protein encoded by this gene is a bifunctional enzyme that channels 1-carbon units from formiminoglutamate, a metabolite of the histidine degradation pathway, to the folate pool. Mutations in this gene are associated with glutamate formiminotransferase deficiency. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 10841 — RefSeq curated summary.

At a glance

• Gene–disease (curated): formiminoglutamic aciduria (Definitive, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 417 total — 5 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 20
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_206965

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3974
Approved symbol	FTCD
Name	formimidoyltransferase cyclodeaminase
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000160282
Ensembl biotype	protein_coding
OMIM	606806
Entrez	10841

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000291670, ENST00000397743, ENST00000397746, ENST00000397748, ENST00000446405, ENST00000460011, ENST00000469240, ENST00000480950, ENST00000483568, ENST00000488577, ENST00000494498, ENST00000498355, ENST00000856709, ENST00000856710, ENST00000856711

RefSeq mRNA: 3 — MANE Select: NM_206965 NM_001320412, NM_006657, NM_206965

CCDS: CCDS13731, CCDS82684

Canonical transcript exons

ENST00000397746 — 14 exons

Exon	Start	End
ENSE00001051131	46151892	46151980
ENSE00003493394	46152907	46153035
ENSE00003506553	46145417	46145578
ENSE00003545440	46137239	46137334
ENSE00003555273	46138880	46138923
ENSE00003580136	46150119	46150250
ENSE00003595298	46150388	46150525
ENSE00003597294	46154149	46154332
ENSE00003606219	46138508	46138646
ENSE00003613882	46146266	46146327
ENSE00003672954	46151558	46151737
ENSE00003681420	46136779	46137073
ENSE00003684003	46145818	46145947
ENSE00003849563	46155470	46155579

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 99.71.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.4172 / max 633.1454, expressed in 147 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190905	1.1867	73
190903	0.2131	68
190906	0.0174	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.71	gold quality
liver	UBERON:0002107	97.25	gold quality
adult mammalian kidney	UBERON:0000082	94.85	gold quality
right testis	UBERON:0004534	94.53	gold quality
left testis	UBERON:0004533	94.41	gold quality
testis	UBERON:0000473	91.22	gold quality
nephron tubule	UBERON:0001231	90.98	gold quality
putamen	UBERON:0001874	90.48	gold quality
kidney epithelium	UBERON:0004819	90.41	gold quality
nucleus accumbens	UBERON:0001882	90.24	gold quality
kidney	UBERON:0002113	90.10	gold quality
right frontal lobe	UBERON:0002810	90.01	gold quality
caudate nucleus	UBERON:0001873	89.65	gold quality
cortex of kidney	UBERON:0001225	88.25	gold quality
metanephros cortex	UBERON:0010533	87.57	gold quality
metanephric glomerulus	UBERON:0004736	87.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.86	gold quality
renal glomerulus	UBERON:0000074	86.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.77	gold quality
anterior cingulate cortex	UBERON:0009835	85.59	gold quality
cingulate cortex	UBERON:0003027	85.50	gold quality
oocyte	CL:0000023	85.01	gold quality
cerebellar vermis	UBERON:0004720	84.99	gold quality
amygdala	UBERON:0001876	84.65	gold quality
metanephros	UBERON:0000081	83.67	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.19	gold quality
pituitary gland	UBERON:0000007	81.69	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.59	gold quality
adenohypophysis	UBERON:0002196	81.54	gold quality
left ovary	UBERON:0002119	81.30	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	4017.93
E-GEOD-131882	yes	3937.21
E-GEOD-36552	yes	55.13
E-ANND-3	yes	5.48
E-CURD-135	no	1140.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting FTCD, 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-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-3918	96.13	64.65	1300

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• Disease-causing mutations have been identified in the FTCD gene in three patients with the putative autosomal recessive disorder glutamate formiminotransferase deficiency. (PMID:12815595)
• Scyl1 interacts with 58K/formiminotransferase cyclodeaminase (FTCD) and golgin p115, and is required for the maintenance of Golgi morphology (PMID:20209057)
• The FTCD promoter is activated by serum depletion according to promoter reporter assays in HEK 293 cells. (PMID:20494980)
• FTCD is a positive regulator of the hypoxia-HIF signaling pathway and has an important role in cell proliferation, metabolism and migration in HepG2 cells (PMID:24686083)
• The formiminotransferase-cyclodeaminase allelic spectrum comprised of 12 distinct variants including 5 missense alterations, an in-frame deletion, two frameshift variants and four nonsense variants with the remaining alterations predicted to affect mRNA processing/stability. (PMID:29178637)
• The rs914246 variant, but not the rs914245 variant, of the FTCD gene modulated accuracy in the task for younger, but not older, people under high working memory (PMID:29927301)
• The Diagnostic Value of Arginase-1, FTCD, and MOC-31 Expression in Early Detection of Hepatocellular Carcinoma (HCC) and in Differentiation Between HCC and Metastatic Adenocarcinoma to the Liver. (PMID:30784016)
• the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD was associated with increased urinary Inorganic arsenics % (P = 8x10-13), increased mono-methylated arsenic % (P = 2x10-16) and decreased di-methylated arsenic % (P = 6x10-23). (PMID:30893314)
• p97 and p47 function in membrane tethering in cooperation with FTCD during mitotic Golgi reassembly. (PMID:33555040)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ftcd	ENSDARG00000007421
mus_musculus	Ftcd	ENSMUSG00000001155
rattus_norvegicus	Ftcd	ENSRNOG00000001261

Paralogs (1): FTCDNL1 (ENSG00000226124)

Protein

Protein identifiers

Formimidoyltransferase-cyclodeaminase — O95954 (reviewed: O95954)

Alternative names: Formiminotransferase-cyclodeaminase, LCHC1

All UniProt accessions (5): O95954, A0A804HKA5, B7WPK3, H7C315, Q49AR5

UniProt curated annotations — full annotation on UniProt →

Function. Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool. Binds and promotes bundling of vimentin filaments originating from the Golgi.

Subunit / interactions. Homooctamer, including four polyglutamate binding sites. The subunits are arranged as a tetramer of dimers, and form a planar ring-shaped structure.

Subcellular location. Cytoplasm. Cytosol. Golgi apparatus. Cytoskeleton. Microtubule organizing center. Centrosome. Centriole.

Disease relevance. Glutamate formiminotransferase deficiency (FIGLU-URIA) [MIM:229100] Autosomal recessive disorder. Features of a severe phenotype, include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and intellectual disability. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematological abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-histidine degradation into L-glutamate; L-glutamate from N-formimidoyl-L-glutamate (transferase route): step 1/1.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. In the C-terminal section; belongs to the cyclodeaminase/cyclohydrolase family. In the N-terminal section; belongs to the formiminotransferase family.

Isoforms (4)

UniProt ID	Names	Canonical?
O95954-1	A	yes
O95954-2	C
O95954-3	D
O95954-4	E

RefSeq proteins (3): NP_001307341, NP_006648, NP_996848* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004227	Formiminotransferase_cat	Domain
IPR007044	Cyclodeamin/CycHdrlase	Domain
IPR012886	Formiminotransferase_N	Domain
IPR013802	Formiminotransferase_C	Domain
IPR022384	FormiminoTrfase_cat_dom_sf	Homologous_superfamily
IPR036178	Formintransfe-cycloase-like_sf	Homologous_superfamily
IPR037064	Formiminotransferase_N_sf	Homologous_superfamily
IPR037070	Formiminotransferase_C_sf	Homologous_superfamily
IPR051623	FTCD	Family

Pfam: PF02971, PF04961, PF07837

Enzyme classification (BRENDA):

• EC 2.1.2.5 — glutamate formimidoyltransferase (BRENDA: 16 organisms, 46 substrates, 44 inhibitors, 25 Km, 10 kcat entries)
• EC 4.3.1.4 — formimidoyltetrahydrofolate cyclodeaminase (BRENDA: 13 organisms, 30 substrates, 16 inhibitors, 14 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

20 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-FORMIMINO-L-GLUTAMATE	2–12	6
5-FORMIMIDOYLTETRAHYDROFOLATE	0.0004–0.0054	4
L-GLUTAMATE	0.034–1.03	4
N-FORMIMIDOYL-L-GLU-L-GLU-L-GLU	0.0007–0.0058	4
(6R,S)-TETRAHYDROFOLATE	0.111–0.148	3
(6S)-TETRAHYDROPTEROYLPENTAGLUTAMATE	0.0017–0.075	2
5-FORMIMINOTETRAHYDROFOLATE	0.026–0.175	2
TETRAHYDROFOLATE	0.1	1
TETRAHYDROPTEROIC ACID	2.5	1
(-)-FORMIMINOTETRAHYDROFOLATE	0.031	1
(-)-FORMIMINOTETRAHYDROPTEROYL-L-ASPARTATE	0.04	1
(-)-FORMIMINOTETRAHYDROPTEROYLTRI-L-GLUTAMATE	0.029	1
(6S)-5-FORMIMINO-5,6,7,8-TETRAHYDROPTEROYLGLUTAM	0.149	1
(6S)-5-FORMIMINO-5,6,7,8-TETRAHYDROPTEROYLHEPTAG	0.0021	1
(6S)-5-FORMIMINO-5,6,7,8-TETRAHYDROPTEROYLHEXAGL	0.0012	1

Catalyzed reactions (Rhea), 2 shown:

• 5-formimidoyltetrahydrofolate + L-glutamate = N-formimidoyl-L-glutamate + (6S)-5,6,7,8-tetrahydrofolate (RHEA:15097)
• 5-formimidoyltetrahydrofolate + 2 H(+) = (6R)-5,10-methenyltetrahydrofolate + NH4(+) (RHEA:22736)

UniProt features (18 total): region of interest 4, splice variant 4, modified residue 4, sequence variant 3, active site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95954-F1	95.30	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 (2): 82 (for formimidoyltransferase activity); 412 (for cyclodeaminase activity)

Post-translational modifications (4): 549, 316, 386, 520

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-70921	Histidine catabolism

MSigDB gene sets: 169 (showing top): GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, GOBP_GLUTAMATE_METABOLIC_PROCESS, CERVERA_SDHB_TARGETS_1_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_ONE_CARBON_POOL_BY_FOLATE, KEGG_HISTIDINE_METABOLISM, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, KOYAMA_SEMA3B_TARGETS_UP, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (5): folic acid-containing compound metabolic process (GO:0006760), cytoskeleton organization (GO:0007010), obsolete L-histidine catabolic process to glutamate and formamide (GO:0019556), obsolete L-histidine catabolic process to glutamate and formate (GO:0019557), obsolete L-histidine metabolic process (GO:0006547)

GO Molecular Function (8): folic acid binding (GO:0005542), microtubule binding (GO:0008017), glutamate formimidoyltransferase activity (GO:0030409), formimidoyltetrahydrofolate cyclodeaminase activity (GO:0030412), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), lyase activity (GO:0016829)

GO Cellular Component (11): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), centriole (GO:0005814), cytosol (GO:0005829), plasma membrane (GO:0005886), smooth endoplasmic reticulum membrane (GO:0030868), extracellular exosome (GO:0070062), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
intracellular membrane-bounded organelle	3
catalytic activity	2
bounding membrane of organelle	2
cellular anatomical structure	2
endomembrane system	2
intracellular membraneless organelle	2
modified amino acid metabolic process	1
pteridine-containing compound metabolic process	1
organelle organization	1
vitamin binding	1
carboxylic acid binding	1
modified amino acid binding	1
heterocyclic compound binding	1
tubulin binding	1
hydroxymethyl-, formyl- and related transferase activity	1
ammonia-lyase activity	1
molecular_function	1
binding	1
Golgi apparatus	1
intracellular anatomical structure	1
microtubule organizing center	1
membrane	1
cell periphery	1
endoplasmic reticulum membrane	1
smooth endoplasmic reticulum	1
extracellular vesicle	1

Protein interactions and networks

STRING

1428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FTCD	DNAL1	Q4LDG9	979
FTCD	HAL	P42357	644
FTCD	AMDHD1	Q96NU7	644
FTCD	MTHFD1	P11586	643
FTCD	SEPSECS	Q9HD40	621
FTCD	UROC1	Q96N76	619
FTCD	GART	P22102	590
FTCD	KIAA1958	Q8N8K9	588
FTCD	MTHFD1L	Q6UB35	571
FTCD	SARDH	Q9UL12	559
FTCD	MTHFD2	P13995	549
FTCD	MTHFR	P42898	535
FTCD	UGDH	O60701	530
FTCD	DMGDH	Q9UI17	527
FTCD	MTHFS	P49914	518

IntAct

38 interactions, top by confidence:

A	B	Type	Score
KASH5	FTCD	psi-mi:“MI:0915”(physical association)	0.560
MED4	FTCD	psi-mi:“MI:0915”(physical association)	0.560
FTCD	KASH5	psi-mi:“MI:0915”(physical association)	0.560
FTCD	MED4	psi-mi:“MI:0915”(physical association)	0.560
FTCD	AGR2	psi-mi:“MI:0915”(physical association)	0.560
HGS	FTCD	psi-mi:“MI:0915”(physical association)	0.560
FTCD	PALS1	psi-mi:“MI:0915”(physical association)	0.560
CCDC183	FTCD	psi-mi:“MI:0915”(physical association)	0.560
PALS1	FTCD	psi-mi:“MI:0915”(physical association)	0.000
HGS	FTCD	psi-mi:“MI:0915”(physical association)	0.000
FTCD	CCDC183	psi-mi:“MI:0915”(physical association)	0.000
FTCD	hspa1a_hspa1b_human-1	psi-mi:“MI:0915”(physical association)	0.000
FTCD	NAA25	psi-mi:“MI:0915”(physical association)	0.000
FTCD	SNRNP70	psi-mi:“MI:0915”(physical association)	0.000
FTCD	BEX3	psi-mi:“MI:0915”(physical association)	0.000
FTCD	EIF4A2	psi-mi:“MI:0915”(physical association)	0.000
FTCD	USP34	psi-mi:“MI:0915”(physical association)	0.000
FTCD	HSPA2	psi-mi:“MI:0915”(physical association)	0.000
FTCD	IDS	psi-mi:“MI:0915”(physical association)	0.000
FTCD	EIF4A1	psi-mi:“MI:0915”(physical association)	0.000
FTCD	DNM1	psi-mi:“MI:0915”(physical association)	0.000
FTCD	GAD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): MED4 (Two-hybrid), CCDC155 (Two-hybrid), FTCD (Two-hybrid), FTCD (Affinity Capture-Western), HIF1A (Affinity Capture-Western), FTCD (Two-hybrid), HGS (Two-hybrid), CCDC183 (Two-hybrid), FTCD (Co-fractionation), GRB14 (Co-fractionation), FTCD (Affinity Capture-MS), ZMYM5 (Two-hybrid), HSPA2 (Two-hybrid), HSPA1A (Two-hybrid), IDS (Two-hybrid)

ESM2 similar proteins: A4FV58, A5GFZ6, A6H791, A6H7F2, D3ZAA9, D4A1R8, D4A7C0, E7F3I6, O43272, O88618, O95954, P49004, Q02053, Q08DB4, Q13144, Q4PF70, Q4R4J2, Q4R579, Q4WT40, Q56XY2, Q58DD9, Q5BJ53, Q5E9M9, Q5R762, Q5RF36, Q5ZKI2, Q66JK4, Q66KF6, Q6DIS1, Q6NS21, Q6PUR6, Q7TSA0, Q7YRA3, Q8BYL4, Q8C166, Q8CHW4, Q8IXI1, Q8JZN7, Q8VEJ1, Q91XD4

Diamond homologs: O88618, O95954, P53603, Q49135, Q54JL3, Q6KZM5, Q91XD4, Q99XR4, Q9HI69, Q9YH58

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	27
Uncertain significance	190
Likely benign	134
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2685664	GRCh37/hg19 21q22.2-22.3(chr21:40681179-48097372)x1	Pathogenic
3248148	NC_000021.8:g.(?47565311)(47575437_?)del	Pathogenic
3619494	NM_206965.2(FTCD):c.613dup (p.Glu205fs)	Pathogenic
3651263	NM_206965.2(FTCD):c.1082_1083insTCGGC (p.Ala362fs)	Pathogenic
632385	NM_206965.2(FTCD):c.763C>T (p.Arg255Ter)	Pathogenic
2579517	NM_206965.2(FTCD):c.184del (p.Ala62fs)	Likely pathogenic
2632941	NM_206965.2(FTCD):c.997C>T (p.Arg333Ter)	Likely pathogenic
2792905	NM_206965.2(FTCD):c.1261-1G>A	Likely pathogenic
2911933	NM_206965.2(FTCD):c.1068_1098+24del	Likely pathogenic
3587700	NM_206965.2(FTCD):c.1543del (p.His515fs)	Likely pathogenic
3587701	NM_206965.2(FTCD):c.1522G>T (p.Glu508Ter)	Likely pathogenic
3587702	NM_206965.2(FTCD):c.1444-1G>A	Likely pathogenic
3587703	NM_206965.2(FTCD):c.1444-2A>C	Likely pathogenic
3587704	NM_206965.2(FTCD):c.1443+1del	Likely pathogenic
3587705	NM_206965.2(FTCD):c.1304+1G>A	Likely pathogenic
3587706	NM_206965.2(FTCD):c.1303dup (p.Arg435fs)	Likely pathogenic
3587707	NM_206965.2(FTCD):c.1081_1096del (p.Ala361fs)	Likely pathogenic
3587708	NM_206965.2(FTCD):c.1085_1087delinsTGGGGTCGCT (p.Ala362fs)	Likely pathogenic
3587709	NM_206965.2(FTCD):c.1072_1085del (p.Ser358fs)	Likely pathogenic
3587710	NM_206965.2(FTCD):c.1061_1062dup (p.Gly355fs)	Likely pathogenic
3587712	NM_206965.2(FTCD):c.1020dup (p.Arg341fs)	Likely pathogenic
3587713	NM_206965.2(FTCD):c.1018del (p.Leu340fs)	Likely pathogenic
3587714	NM_206965.2(FTCD):c.998_1002del (p.Arg333fs)	Likely pathogenic
3587715	NM_206965.2(FTCD):c.993del (p.Glu332fs)	Likely pathogenic
3587716	NM_206965.2(FTCD):c.939C>A (p.Cys313Ter)	Likely pathogenic
3587717	NM_206965.2(FTCD):c.673dup (p.Tyr225fs)	Likely pathogenic
3587719	NM_206965.2(FTCD):c.333del (p.Phe111fs)	Likely pathogenic
3587720	NM_206965.2(FTCD):c.330dup (p.Phe111fs)	Likely pathogenic
3587721	NM_206965.2(FTCD):c.299dup (p.Ser100fs)	Likely pathogenic
3587722	NM_206965.2(FTCD):c.54+2T>A	Likely pathogenic

SpliceAI

3140 predictions. Top by Δscore:

Variant	Effect	Δscore
21:46137234:CTCA:C	donor_loss	1.0000
21:46137236:CA:C	donor_loss	1.0000
21:46137238:C:A	donor_loss	1.0000
21:46137248:AAATG:A	donor_gain	1.0000
21:46138642:TGCGC:T	acceptor_gain	1.0000
21:46138643:GCGC:G	acceptor_gain	1.0000
21:46138644:CGC:C	acceptor_gain	1.0000
21:46138644:CGCC:C	acceptor_gain	1.0000
21:46138647:C:CC	acceptor_gain	1.0000
21:46138648:T:G	acceptor_loss	1.0000
21:46145412:CTCA:C	donor_loss	1.0000
21:46145413:TCAC:T	donor_loss	1.0000
21:46145414:CA:C	donor_loss	1.0000
21:46145415:A:AC	donor_gain	1.0000
21:46145415:A:AT	donor_loss	1.0000
21:46145416:C:CC	donor_gain	1.0000
21:46150085:C:A	donor_gain	1.0000
21:46150099:T:TA	donor_gain	1.0000
21:46150138:T:TA	donor_gain	1.0000
21:46150382:GCTCA:G	donor_loss	1.0000
21:46150383:CTCAC:C	donor_loss	1.0000
21:46150384:TCACC:T	donor_loss	1.0000
21:46150385:CA:C	donor_loss	1.0000
21:46150386:A:C	donor_loss	1.0000
21:46150387:C:A	donor_loss	1.0000
21:46150526:C:CC	acceptor_gain	1.0000
21:46151916:C:A	donor_gain	1.0000
21:46151981:C:CC	acceptor_gain	1.0000
21:46152902:CTCA:C	donor_loss	1.0000
21:46152903:TCACC:T	donor_loss	1.0000

AlphaMissense

3466 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:46155494:G:C	N10K	0.991
21:46155494:G:T	N10K	0.991
21:46153003:A:G	C91R	0.990
21:46151658:C:A	R179M	0.989
21:46150463:C:A	Q233H	0.987
21:46150463:C:G	Q233H	0.987
21:46151636:G:C	N186K	0.987
21:46151636:G:T	N186K	0.987
21:46153009:C:G	D89H	0.987
21:46154250:C:G	R46P	0.987
21:46150492:A:G	W224R	0.986
21:46150492:A:T	W224R	0.986
21:46153001:G:C	C91W	0.986
21:46150451:A:C	N237K	0.985
21:46150451:A:T	N237K	0.985
21:46153028:G:C	H82Q	0.985
21:46153028:G:T	H82Q	0.985
21:46150449:A:G	L238P	0.984
21:46150467:G:T	A232D	0.984
21:46153030:G:C	H82D	0.984
21:46154251:G:T	R46S	0.984
21:46151658:C:G	R179T	0.983
21:46152996:A:G	F93S	0.983
21:46153018:C:A	G86W	0.983
21:46151643:G:T	A184D	0.982
21:46155498:G:T	P9H	0.982
21:46153007:G:C	D89E	0.981
21:46153007:G:T	D89E	0.981
21:46151657:C:A	R179S	0.980
21:46151657:C:G	R179S	0.980

dbSNP variants (sampled 300 via entrez): RS1000084211 (21:46141011 C>G), RS1000234163 (21:46145573 C>G,T), RS1000275671 (21:46157263 T>C), RS1000375560 (21:46150402 A>C,T), RS1000429191 (21:46153475 G>A), RS1000434822 (21:46141168 C>T), RS1000467927 (21:46141792 G>A,C,T), RS1000558227 (21:46144133 A>G), RS1000594505 (21:46138286 C>A), RS1000663795 (21:46150636 TGGGTGG>T), RS1000709537 (21:46157025 G>A), RS1000812210 (21:46146210 G>C,T), RS1000845153 (21:46146044 A>T), RS1000868509 (21:46156772 T>C), RS1001041657 (21:46141869 C>T)

Disease associations

OMIM: gene MIM:606806 | disease phenotypes: MIM:229100

GenCC curated gene-disease

Disease	Classification	Inheritance
formiminoglutamic aciduria	Definitive	Autosomal recessive

Mondo (3): formiminoglutamic aciduria (MONDO:0009240), intellectual disability (MONDO:0001071), myoepithelial tumor (MONDO:0002380)

Orphanet (2): Formiminoglutamic aciduria (Orphanet:51208), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001510	Growth delay
HP:0001631	Atrial septal defect
HP:0001889	Megaloblastic anemia
HP:0001903	Anemia
HP:0003355	Aminoaciduria
HP:0003612	Positive ferric chloride test
HP:0004821	Hypersegmentation of neutrophil nuclei
HP:0010864	Severe intellectual disability
HP:0010904	Abnormal circulating histidine concentration
HP:0011342	Mild global developmental delay
HP:0012335	Abnormality of folate metabolism
HP:0012379	Abnormal circulating enzyme concentration or activity
HP:0012758	Neurodevelopmental delay
HP:0032164	Increased blood folate concentration
HP:0034742	Elevated urinary formiminoglutamic acid level
HP:0500170	Abnormal concentration of acylcarnitine in the urine

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006585_2453	Blood protein levels	2.000000e-08
GCST010002_78	Refractive error	2.000000e-36
GCST011383_1	Mastocytosis	1.000000e-09

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009208	Myoepithelioma	C04.557.435.585
C537425	Glutamate formiminotransferase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	increases methylation, decreases expression, increases expression	2
aristolochic acid I	increases expression	1
fluorene-9-bisphenol	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
periodate-oxidized adenosine	affects expression	1
aflatoxin B2	increases methylation	1
perfluorodecanoic acid	affects expression, affects methylation	1
K 7174	decreases expression	1
abrine	increases expression	1
Resveratrol	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Carbamazepine	affects expression	1
Copper	affects binding, decreases expression	1
Diclofenac	affects expression	1
Disulfiram	affects binding, decreases expression	1
Isoniazid	decreases expression	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases expression	1
Cadmium Chloride	increases expression	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability