Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome

Summary

Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (MONDO:0014558) is a disease caused by KAT6A (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KAT6A (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 197
• Phenotypes (HPO): 39

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		76	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000219	Thin upper lip vermilion	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000341	Narrow forehead	Very frequent (80-99%)
HP:0000426	Prominent nasal bridge	Very frequent (80-99%)
HP:0000455	Broad nasal tip	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002465	Poor speech	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000308	Microretrognathia	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001357	Plagiocephaly	Frequent (30-79%)
HP:0001363	Craniosynostosis	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002643	Neonatal respiratory distress	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0003552	Muscle stiffness	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0100704	Cerebral visual impairment	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001601	Laryngomalacia	Occasional (5-29%)
HP:0002566	Intestinal malrotation	Occasional (5-29%)
HP:0004467	Preauricular pit	Occasional (5-29%)
HP:0007678	Lacrimal duct stenosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome
Mondo ID	MONDO:0014558
OMIM	616268
Orphanet	457193
DOID	DOID:0070062
UMLS	C4225396
MedGen	903767
GARD	0017797
NORD	1954
Is cancer (heuristic)	no

Also known as: Arboleda-Tham syndrome · autosomal dominant intellectual disability 32 · autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome · intellectual disability, autosomal dominant 32 · intellectual disability, autosomal dominant type 32 · KAT6A Syndrome · mental retardation, autosomal dominant 32 · mental retardation, autosomal dominant type 32 · MRD32

Data availability: 197 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome

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, AICA-ribosiduria, 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, 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

197 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 52 pathogenic, 41 likely pathogenic, 29 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 7 benign/likely benign, 3 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034308	NM_006766.5(KAT6A):c.2463del (p.Asn821fs)	KAT6A	Pathogenic	criteria provided, single submitter
1048764	NM_006766.5(KAT6A):c.1146_1147insG (p.Tyr383fs)	KAT6A	Pathogenic	criteria provided, single submitter
1082502	NM_006766.5:c.3411del	KAT6A	Pathogenic	no assertion criteria provided
1285569	NM_006766.5(KAT6A):c.1405C>T (p.Arg469Ter)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
1323134	NM_006766.5(KAT6A):c.4398_4399del (p.Gln1467fs)	KAT6A	Pathogenic	criteria provided, single submitter
1325410	NM_006766.5(KAT6A):c.1312C>T (p.Arg438Ter)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
162616	NM_006766.5(KAT6A):c.3116_3117del (p.Ile1038_Ser1039insTer)	KAT6A	Pathogenic	criteria provided, single submitter
1697352	NM_006766.5(KAT6A):c.376A>T (p.Lys126Ter)	KAT6A	Pathogenic	criteria provided, single submitter
1698914	NM_006766.5(KAT6A):c.1133C>G (p.Ser378Ter)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
180229	NM_006766.5(KAT6A):c.3385C>T (p.Arg1129Ter)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
180230	NM_006766.5(KAT6A):c.3070C>T (p.Arg1024Ter)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
1805333	NM_006766.5(KAT6A):c.3631_3632del (p.Thr1210_Val1211insTer)	KAT6A	Pathogenic	criteria provided, single submitter
1805338	NM_006766.5(KAT6A):c.3377del (p.Ser1126fs)	KAT6A	Pathogenic	criteria provided, single submitter
1805561	NM_006766.5(KAT6A):c.3820G>T (p.Glu1274Ter)	KAT6A	Pathogenic	criteria provided, single submitter
1805653	NM_006766.5(KAT6A):c.3399_3400dup (p.Lys1134fs)	KAT6A	Pathogenic	criteria provided, single submitter
180678	NM_006766.5(KAT6A):c.3879dup (p.Glu1294fs)	KAT6A	Pathogenic	no assertion criteria provided
2227868	NM_006766.5(KAT6A):c.4297C>T (p.Gln1433Ter)	KAT6A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2430855	NM_006766.5(KAT6A):c.3348_3349dup (p.Asp1117fs)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
2584389	NM_006766.5(KAT6A):c.5505_5506del (p.Asn1836fs)	KAT6A	Pathogenic	criteria provided, single submitter
2663817	NM_006766.5(KAT6A):c.2927del (p.Gly976fs)	KAT6A	Pathogenic	criteria provided, single submitter
2663859	NM_006766.5(KAT6A):c.3344_3350del (p.Asp1115fs)	KAT6A	Pathogenic	criteria provided, single submitter
280246	NM_006766.5(KAT6A):c.3661G>T (p.Glu1221Ter)	KAT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
3062049	NM_006766.5(KAT6A):c.4980del (p.Gln1660fs)	KAT6A	Pathogenic	criteria provided, single submitter
3062135	NM_006766.5(KAT6A):c.3824_3828del (p.Glu1275fs)	KAT6A	Pathogenic	criteria provided, single submitter
3254794	NM_006766.5(KAT6A):c.441dup (p.Arg148fs)	KAT6A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338566	NM_006766.5(KAT6A):c.3898dup (p.Glu1300fs)	KAT6A	Pathogenic	criteria provided, single submitter
369686	NM_006766.5(KAT6A):c.4254_4257del (p.Glu1419fs)	KAT6A	Pathogenic	criteria provided, single submitter
3895479	NM_006766.5(KAT6A):c.3147dup (p.Glu1050Ter)	KAT6A	Pathogenic	criteria provided, single submitter
3906970	NM_006766.5(KAT6A):c.2260C>T (p.Gln754Ter)	KAT6A	Pathogenic	criteria provided, single submitter
4056377	NM_006766.5(KAT6A):c.4421del (p.Cys1474fs)	KAT6A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
KAT6A	Definitive	Autosomal dominant	autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KAT6A	Orphanet:370026	Acute myeloid leukemia with t(8;16)(p11;p13) translocation
KAT6A	Orphanet:457193	KAT6-related intellectual disability-craniofacial anomalies-cardiac defects syndrome
COG6	Orphanet:363523	Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome
COG6	Orphanet:464443	COG6-CGD
CCM2	Orphanet:221061	Familial cerebral cavernous malformation

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KAT6A	HGNC:13013	ENSG00000083168	Q92794	Histone acetyltransferase KAT6A	gencc,clinvar
COG6	HGNC:18621	ENSG00000133103	Q9Y2V7	Conserved oligomeric Golgi complex subunit 6	clinvar
CCM2	HGNC:21708	ENSG00000136280	Q9BSQ5	Cerebral cavernous malformations 2 protein	clinvar
OSM	HGNC:8506	ENSG00000099985	P13725	Oncostatin-M	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KAT6A	Histone acetyltransferase KAT6A	Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro).
COG6	Conserved oligomeric Golgi complex subunit 6	Required for normal Golgi function.
CCM2	Cerebral cavernous malformations 2 protein	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.
OSM	Oncostatin-M	Growth regulator.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.0

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
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KAT6A	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
COG6	Other/Unknown	no		COG6, COG6_N, COG6_C
CCM2	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Malcavernin
OSM	Other/Unknown	no		Leukemia_IF/oncostatin, 4_helix_cytokine-like_core, Leukemia_IF/oncostatin_CS

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
globus pallidus	1
medial globus pallidus	1
nipple	1
calcaneal tendon	1
secondary oocyte	1
tibia	1
anterior cingulate cortex	1
nucleus accumbens	1
putamen	1
bone marrow cell	1
pancreatic ductal cell	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KAT6A	299	ubiquitous	marker	nipple, medial globus pallidus, globus pallidus
COG6	254	ubiquitous	marker	secondary oocyte, tibia, calcaneal tendon
CCM2	243	ubiquitous	marker	putamen, nucleus accumbens, anterior cingulate cortex
OSM	151	broad	marker	pancreatic ductal cell, bone marrow cell, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COG6	2,336
OSM	1,864
CCM2	1,600
KAT6A	649

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KAT6A	Q92794	21
CCM2	Q9BSQ5	8
OSM	P13725	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COG6	Q9Y2V7	86.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IL-6-type cytokine receptor ligand interactions	1	211.5×	0.046	OSM
Regulation of TP53 Activity through Acetylation	1	152.3×	0.046	KAT6A
Intra-Golgi traffic	1	86.5×	0.048	COG6
Retrograde transport at the Trans-Golgi-Network	1	73.2×	0.048	COG6
Regulation of TP53 Activity	1	44.3×	0.057	KAT6A
COPI-mediated anterograde transport	1	36.6×	0.057	COG6
Interleukin-4 and Interleukin-13 signaling	1	34.3×	0.057	OSM
Chromatin organization	1	27.2×	0.057	KAT6A
HATs acetylate histones	1	26.4×	0.057	KAT6A
Chromatin modifying enzymes	1	24.1×	0.057	KAT6A
Transcriptional Regulation by TP53	1	20.7×	0.061	KAT6A
RNA Polymerase II Transcription	1	7.5×	0.149	KAT6A
Gene expression (Transcription)	1	6.0×	0.171	KAT6A
Generic Transcription Pathway	1	5.0×	0.186	KAT6A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endothelial cell development	1	1053.2×	0.011	CCM2
oncostatin-M-mediated signaling pathway	1	1053.2×	0.011	OSM
blood vessel endothelial cell differentiation	1	842.6×	0.011	CCM2
venous blood vessel morphogenesis	1	601.9×	0.011	CCM2
regulation of developmental process	1	601.9×	0.011	KAT6A
retrograde transport, vesicle recycling within Golgi	1	468.1×	0.011	COG6
negative regulation of hormone secretion	1	468.1×	0.011	OSM
pericardium development	1	468.1×	0.011	CCM2
endothelial tube morphogenesis	1	468.1×	0.011	CCM2
regulation of hematopoietic stem cell differentiation	1	383.0×	0.011	OSM
regulation of hemopoiesis	1	383.0×	0.011	KAT6A
positive regulation of acute inflammatory response	1	351.1×	0.011	OSM
protein acetylation	1	351.1×	0.011	KAT6A
endothelium development	1	324.1×	0.011	CCM2
positive regulation of peptidyl-tyrosine phosphorylation	1	200.6×	0.015	OSM
positive regulation of peptidyl-serine phosphorylation	1	191.5×	0.015	OSM
positive regulation of tyrosine phosphorylation of STAT protein	1	183.2×	0.015	OSM
stress-activated MAPK cascade	1	175.5×	0.015	CCM2
myeloid cell differentiation	1	162.0×	0.015	KAT6A
cell-cell junction organization	1	156.0×	0.015	CCM2
positive regulation of interleukin-17 production	1	150.5×	0.015	OSM
chromosome organization	1	145.3×	0.015	KAT6A
intra-Golgi vesicle-mediated transport	1	131.7×	0.016	COG6
regulation of angiogenesis	1	105.3×	0.019	CCM2
regulation of signal transduction by p53 class mediator	1	95.8×	0.020	KAT6A
inner ear development	1	93.6×	0.020	CCM2
positive regulation of cell division	1	84.3×	0.021	OSM
cellular senescence	1	73.9×	0.023	KAT6A
vasculogenesis	1	63.8×	0.026	CCM2
integrin-mediated signaling pathway	1	40.1×	0.040	CCM2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KAT6A	0	0
COG6	0	0
CCM2	0	0
OSM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KAT6A	42	Binding:39, Functional:3
COG6	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6A	2.3.1.48	histone acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	0
E	Difficult family or no structure, no drug	4	KAT6A, COG6, CCM2, OSM

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KAT6A	42	—
COG6	2	—
CCM2	0	—
OSM	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.