AICA-ribosiduria

Summary

AICA-ribosiduria (MONDO:0012099) is a disease caused by ATIC (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATIC (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 28
• Phenotypes (HPO): 10
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000063	Fused labia minora	Very frequent (80-99%)
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000219	Thin upper lip vermilion	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0007875	Congenital blindness	Very frequent (80-99%)
HP:0008665	Clitoral hypertrophy	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011220	Prominent forehead	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	AICA-ribosiduria
Mondo ID	MONDO:0012099
MeSH	C563876
OMIM	608688
Orphanet	250977
SNOMED CT	725289009
UMLS	C1837530
MedGen	332474
GARD	0013781
Is cancer (heuristic)	no

Also known as: 5-amino-4-imidazole carboxamide ribosiduria · AICA-ribosiduria due to ATIC deficiency · ATIC deficiency

Data availability: 28 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › AICA-ribosiduria

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

28 retrieved; paginated sample, class counts are floors:

8 benign, 7 uncertain significance, 4 benign/likely benign, 4 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
666360	NM_004044.7(ATIC):c.1654A>T (p.Lys552Ter)	ATIC	Pathogenic	no assertion criteria provided
7811	NM_004044.7(ATIC):c.131delinsGGA (p.Ala44fs)	ATIC	Pathogenic	no assertion criteria provided
4796628	NM_004044.7(ATIC):c.371T>C (p.Ile124Thr)	ATIC	Likely pathogenic	criteria provided, single submitter
4845921	NM_004044.7(ATIC):c.1070del (p.Lys357fs)	ATIC	Likely pathogenic	criteria provided, single submitter
4849484	NM_004044.7(ATIC):c.1227+2T>C	ATIC	Likely pathogenic	criteria provided, single submitter
801894	NM_004044.7(ATIC):c.1085A>G (p.Tyr362Cys)	ATIC	Likely pathogenic	criteria provided, single submitter
2439310	NM_004044.7(ATIC):c.131delinsGCA (p.Ala44fs)	ATIC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7810	NM_004044.7(ATIC):c.1277A>G (p.Lys426Arg)	ATIC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030737	NM_004044.7(ATIC):c.1474G>T (p.Asp492Tyr)	ATIC	Uncertain significance	criteria provided, single submitter
3585398	NM_004044.7(ATIC):c.1466A>G (p.Asn489Ser)	ATIC	Uncertain significance	criteria provided, single submitter
3780143	NM_004044.7(ATIC):c.25T>C (p.Phe9Leu)	ATIC	Uncertain significance	criteria provided, single submitter
548528	NM_004044.7(ATIC):c.1751A>G (p.His584Arg)	ATIC	Uncertain significance	criteria provided, multiple submitters, no conflicts
561183	NM_004044.7(ATIC):c.794del (p.Phe265fs)	ATIC	Uncertain significance	no assertion criteria provided
638424	NM_004044.7(ATIC):c.548C>A (p.Ala183Glu)	ATIC	Uncertain significance	criteria provided, multiple submitters, no conflicts
666359	NM_004044.7(ATIC):c.406G>A (p.Ala136Thr)	ATIC	Uncertain significance	criteria provided, single submitter
1192365	NM_004044.7(ATIC):c.-218A>G	ATIC	Benign	criteria provided, multiple submitters, no conflicts
1192366	NM_004044.7(ATIC):c.-59T>G	ATIC	Benign	criteria provided, multiple submitters, no conflicts
1192367	NM_004044.7(ATIC):c.147-111A>T	ATIC	Benign	criteria provided, multiple submitters, no conflicts
1192368	NM_004044.7(ATIC):c.380-19A>C	ATIC	Benign	criteria provided, multiple submitters, no conflicts
1192369	NM_004044.7(ATIC):c.1098+60C>G	ATIC	Benign	criteria provided, multiple submitters, no conflicts
1192370	NM_004044.7(ATIC):c.1228-30A>G	ATIC	Benign	criteria provided, multiple submitters, no conflicts
1192371	NM_004044.7(ATIC):c.1503+48A>T	ATIC	Benign	criteria provided, multiple submitters, no conflicts
445305	NM_004044.7(ATIC):c.1670C>T (p.Ala557Val)	ATIC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
445428	NM_004044.7(ATIC):c.380-18G>A	ATIC	Likely benign	criteria provided, multiple submitters, no conflicts
775810	NM_004044.7(ATIC):c.1499G>A (p.Gly500Asp)	ATIC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
784586	NM_004044.7(ATIC):c.1494C>G (p.Thr498=)	ATIC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
785991	NM_004044.7(ATIC):c.5C>T (p.Ala2Val)	ATIC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
801893	NM_004044.7(ATIC):c.347C>G (p.Thr116Ser)	ATIC	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ATIC	Definitive	Autosomal recessive	AICA-ribosiduria	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATIC	Orphanet:250977	AICA-ribosiduria

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
ATIC	HGNC:794	ENSG00000138363	P31939	Bifunctional purine biosynthesis protein ATIC	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATIC	Bifunctional purine biosynthesis protein ATIC	Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis.

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)
ATIC	Enzyme (other)	yes	2.1.2.3	PurH-like, MGS-like_dom, Cytidine_deaminase-like

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
mucosa of transverse colon	1
rectum	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATIC	290	ubiquitous	marker	mucosa of transverse colon, stromal cell of endometrium, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATIC	3,960

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATIC	P31939	5

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
Purine ribonucleoside monophosphate biosynthesis	1	1038.2×	0.002	ATIC
Signaling by ALK fusions and activated point mutants	1	150.3×	0.007	ATIC

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
dihydrofolate metabolic process	1	5617.3×	9e-04	ATIC
‘de novo’ IMP biosynthetic process	1	2808.7×	9e-04	ATIC
tetrahydrofolate biosynthetic process	1	2808.7×	9e-04	ATIC
brainstem development	1	2106.5×	9e-04	ATIC
‘de novo’ AMP biosynthetic process	1	2106.5×	9e-04	ATIC
‘de novo’ XMP biosynthetic process	1	2106.5×	9e-04	ATIC
GMP biosynthetic process	1	1872.4×	9e-04	ATIC
cellular response to interleukin-7	1	1296.3×	0.001	ATIC
animal organ regeneration	1	601.9×	0.002	ATIC
nucleobase-containing compound metabolic process	1	526.6×	0.002	ATIC
cerebellum development	1	358.6×	0.003	ATIC
cerebral cortex development	1	205.5×	0.005	ATIC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATIC	PEMETREXED

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATIC	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATIC	95	Binding:95

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATIC	2.1.2.3, 3.5.4.10	phosphoribosylaminoimidazolecarboxamide formyltransferase, IMP cyclohydrolase

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

3 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.

Compound	Max phase	Cohort target (bioactivity)
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATIC
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06845501	Not specified	RECRUITING	Purine Supplementation in Patients With AICA-Ribosiduria