Formiminoglutamic aciduria

Summary

Formiminoglutamic aciduria (MONDO:0009240) is a disease caused by FTCD (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: FTCD (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 298
• Phenotypes (HPO): 13

Clinical features

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0010904	Abnormal circulating histidine concentration	Very frequent (80-99%)
HP:0012335	Abnormality of folate metabolism	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0032164	Increased blood folate concentration	Frequent (30-79%)
HP:0500170	Abnormal concentration of acylcarnitine in the urine	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001889	Megaloblastic anemia	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0011342	Mild global developmental delay	Occasional (5-29%)
HP:0012758	Neurodevelopmental delay	Occasional (5-29%)
HP:0000717	Autism	Very rare (<1-4%)
HP:0001631	Atrial septal defect	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	formiminoglutamic aciduria
Mondo ID	MONDO:0009240
MeSH	C537425
OMIM	229100
Orphanet	51208
DOID	DOID:0111679
ICD-11	664824338
SNOMED CT	59761008
UMLS	C0268609
MedGen	82823
GARD	0009279
Is cancer (heuristic)	no

Also known as: Arakawa syndrome 1 · formiminoglutamic acidemia · formiminoglutamic aciduria · Formiminoglutamicaciduria (FIGLU-Uria) · formiminotransferase cyclodeaminase deficiency · formiminotransferase deficiency syndrome · FTCD deficiency · glutamate formiminotransferase deficiency

Data availability: 298 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › macrocytic anemia › megaloblastic anemia › formiminoglutamic aciduria

Related subtypes (5): pernicious anemia, hereditary folate malabsorption, Imerslund-Grasbeck syndrome, constitutional megaloblastic anemia with severe neurologic disease, vitamin B12- and folate-independent constitutional megaloblastic anemia

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

298 retrieved; paginated sample, class counts are floors:

120 likely benign, 92 uncertain significance, 32 benign, 27 likely pathogenic, 9 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 6 pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071137	NM_206965.2(FTCD):c.293dup (p.Val99fs)	FTCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194395	NM_206965.2(FTCD):c.1607T>A (p.Leu536Ter)	FTCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3248148	NC_000021.8:g.(?47565311)(47575437_?)del	FTCD	Pathogenic	criteria provided, single submitter
3587711	NM_206965.2(FTCD):c.1031_1061del (p.Val344fs)	FTCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3619494	NM_206965.2(FTCD):c.613dup (p.Glu205fs)	FTCD	Pathogenic	criteria provided, single submitter
3651263	NM_206965.2(FTCD):c.1082_1083insTCGGC (p.Ala362fs)	FTCD	Pathogenic	criteria provided, single submitter
4019	NM_206965.2(FTCD):c.990dup (p.Pro331fs)	FTCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488890	NM_206965.2(FTCD):c.211C>T (p.Arg71Ter)	FTCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632385	NM_206965.2(FTCD):c.763C>T (p.Arg255Ter)	FTCD	Pathogenic	criteria provided, multiple submitters, no conflicts
2800589	NM_206965.2(FTCD):c.372C>G (p.Tyr124Ter)	FTCD-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3669848	NM_206965.2(FTCD):c.492del (p.Ser165fs)	FTCD-AS1	Pathogenic	criteria provided, single submitter
459967	NM_206965.2(FTCD):c.378C>G (p.Tyr126Ter)	FTCD-AS1	Pathogenic	criteria provided, single submitter
2579517	NM_206965.2(FTCD):c.184del (p.Ala62fs)	FTCD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2792905	NM_206965.2(FTCD):c.1261-1G>A	FTCD	Likely pathogenic	criteria provided, single submitter
2911933	NM_206965.2(FTCD):c.1068_1098+24del	FTCD	Likely pathogenic	criteria provided, single submitter
3587700	NM_206965.2(FTCD):c.1543del (p.His515fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587701	NM_206965.2(FTCD):c.1522G>T (p.Glu508Ter)	FTCD	Likely pathogenic	criteria provided, single submitter
3587702	NM_206965.2(FTCD):c.1444-1G>A	FTCD	Likely pathogenic	criteria provided, single submitter
3587703	NM_206965.2(FTCD):c.1444-2A>C	FTCD	Likely pathogenic	criteria provided, single submitter
3587704	NM_206965.2(FTCD):c.1443+1del	FTCD	Likely pathogenic	criteria provided, single submitter
3587705	NM_206965.2(FTCD):c.1304+1G>A	FTCD	Likely pathogenic	criteria provided, single submitter
3587706	NM_206965.2(FTCD):c.1303dup (p.Arg435fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587707	NM_206965.2(FTCD):c.1081_1096del (p.Ala361fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587708	NM_206965.2(FTCD):c.1085_1087delinsTGGGGTCGCT (p.Ala362fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587709	NM_206965.2(FTCD):c.1072_1085del (p.Ser358fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587710	NM_206965.2(FTCD):c.1061_1062dup (p.Gly355fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587712	NM_206965.2(FTCD):c.1020dup (p.Arg341fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587713	NM_206965.2(FTCD):c.1018del (p.Leu340fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587714	NM_206965.2(FTCD):c.998_1002del (p.Arg333fs)	FTCD	Likely pathogenic	criteria provided, single submitter
3587715	NM_206965.2(FTCD):c.993del (p.Glu332fs)	FTCD	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
FTCD	Definitive	Autosomal recessive	formiminoglutamic aciduria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FTCD	Orphanet:51208	Formiminoglutamic aciduria

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FTCD	HGNC:3974	ENSG00000160282	O95954	Formimidoyltransferase-cyclodeaminase	gencc,clinvar
FTCD-AS1	HGNC:40243	ENSG00000237338		FTCD antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FTCD	Formimidoyltransferase-cyclodeaminase	Folate-dependent enzyme, that displays both transferase and deaminase activity.

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)
FTCD	Enzyme (other)	yes	2.1.2.5	Formiminotransferase_cat, Cyclodeamin/CycHdrlase, Formiminotransferase_N
FTCD-AS1	Other/Unknown	no

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
liver	2
right lobe of liver	2
adult mammalian kidney	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FTCD	179	tissue_specific	marker	right lobe of liver, liver, adult mammalian kidney
FTCD-AS1	101		yes	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FTCD	1,495
FTCD-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FTCD	O95954	95.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Histidine catabolism	1	1142.0×	9e-04	FTCD

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
folic acid-containing compound metabolic process	1	4213.0×	3e-04	FTCD
obsolete L-histidine catabolic process to glutamate and formamide	1	4213.0×	3e-04	FTCD
obsolete L-histidine catabolic process to glutamate and formate	1	4213.0×	3e-04	FTCD
cytoskeleton organization	1	132.7×	0.008	FTCD

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
FTCD	0	0
FTCD-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FTCD	2.1.2.5, 4.3.1.4	glutamate formimidoyltransferase, formimidoyltetrahydrofolate cyclodeaminase

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	0
D	Druggable family + AlphaFold only, no drug	1	FTCD
E	Difficult family or no structure, no drug	1	FTCD-AS1

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)
FTCD	0	—
FTCD-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.