Coffin-Siris syndrome 1

Summary

Coffin-Siris syndrome 1 (MONDO:0007617) is a disease caused by ARID1B (GenCC Definitive), with 13 cohort genes. The dominant Reactome pathway is Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF) (6 cohort genes).

At a glance

• Causal gene: ARID1B (GenCC Definitive)
• Cohort genes: 13
• ClinVar variants: 542

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Coffin-Siris syndrome 1
Mondo ID	MONDO:0007617
MeSH	C538391
OMIM	135900, 609943, 614562
DOID	DOID:0070042
UMLS	C3281201
MedGen	482831
GARD	0015072
Is cancer (heuristic)	no

Also known as: ARID1B-related BAFopathy · COFFIN-SIRIS syndrome · COFFIN-SIRIS syndrome 1 · Coffin-Siris syndrome 1 · CSS · CSS1 · fifth digit syndrome · hypertrichosis, hyperkeratosis, intellectual disability, and distinctive facial features · hypertrichosis, hyperkeratosis, mental retardation, and distinctive facial features · intellectual disability, autosomal dominant 12 · mental retardation, autosomal dominant 12 · mental retardation, autosomal dominant type 12 · MRD12

Data availability: 542 ClinVar variants · 4 GenCC gene-disease records · 18 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Coffin-Siris syndrome 1

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

542 retrieved; paginated sample, class counts are floors:

193 pathogenic, 108 uncertain significance, 95 likely pathogenic, 62 conflicting classifications of pathogenicity, 41 benign/likely benign, 25 pathogenic/likely pathogenic, 9 benign, 6 likely benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
561258	46,XX,der(6)(q25.1,q28)dn.seq[GRCh37/hg19]der(6)(6pter->6q25.2(+)(154768571)::q25.2(+)(154778901),q25.2(+)154778992::q25.2(-)(154774048),q25.2(-)(154768571)::q25.2(-)(154768571),q25.1(-)(~151443183-151443483))dn	AIRN	Pathogenic	no assertion criteria provided
30292	NM_006015.6(ARID1A):c.31_56del (p.Ser11fs)	ARID1A	Pathogenic	criteria provided, multiple submitters, no conflicts
30294	NM_006015.6(ARID1A):c.4003C>T (p.Arg1335Ter)	ARID1A	Pathogenic	criteria provided, single submitter
452118	NM_006015.6(ARID1A):c.3033G>T (p.Leu1011Phe)	ARID1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033954	NM_001374828.1(ARID1B):c.3126del (p.Met1043fs)	ARID1B	Pathogenic	criteria provided, single submitter
1164017	NM_001374828.1(ARID1B):c.6497dup (p.Ser2166fs)	ARID1B	Pathogenic	no assertion criteria provided
1164018	NM_001374828.1(ARID1B):c.3247_3248del (p.Leu1083fs)	ARID1B	Pathogenic	no assertion criteria provided
1174076	NM_001374828.1(ARID1B):c.3345G>C (p.Lys1115Asn)	ARID1B	Pathogenic	no assertion criteria provided
1177361	NM_001374828.1(ARID1B):c.3585G>A (p.Trp1195Ter)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1184336	NM_001374828.1(ARID1B):c.4150C>T (p.Gln1384Ter)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1184937	NM_001374828.1(ARID1B):c.4870dup (p.Val1624fs)	ARID1B	Pathogenic	criteria provided, single submitter
1185060	NM_001374828.1(ARID1B):c.2773A>T (p.Arg925Ter)	ARID1B	Pathogenic	no assertion criteria provided
1199407	NM_001374828.1(ARID1B):c.1293_1317del (p.Ala433fs)	ARID1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1275757	NM_001374828.1(ARID1B):c.1574del (p.Ser525fs)	ARID1B	Pathogenic	no assertion criteria provided
1319938	NM_001374828.1(ARID1B):c.4921C>T (p.Gln1641Ter)	ARID1B	Pathogenic	no assertion criteria provided
1320053	NM_001374828.1(ARID1B):c.6094del (p.Gln2032fs)	ARID1B	Pathogenic	criteria provided, single submitter
1320109	NM_001374828.1(ARID1B):c.1560C>G (p.Tyr520Ter)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1320276	NM_001374828.1(ARID1B):c.5218C>T (p.Gln1740Ter)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1323409	NM_001374828.1(ARID1B):c.4478del (p.Pro1493fs)	ARID1B	Pathogenic	criteria provided, single submitter
1323410	NM_001374828.1(ARID1B):c.6377dup (p.Val2128fs)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1333862	NM_001374828.1(ARID1B):c.5264-2A>G	ARID1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334424	NM_001374828.1(ARID1B):c.2058del (p.Gln686fs)	ARID1B	Pathogenic	no assertion criteria provided
1334504	NM_001374828.1(ARID1B):c.4215del (p.Phe1405fs)	ARID1B	Pathogenic	criteria provided, single submitter
1343135	NM_001374828.1(ARID1B):c.6236C>G (p.Ser2079Ter)	ARID1B	Pathogenic	criteria provided, single submitter
1344548	NM_001374828.1(ARID1B):c.5263+1G>T	ARID1B	Pathogenic	criteria provided, single submitter
1527910	NM_001374828.1(ARID1B):c.2762G>T (p.Gly921Val)	ARID1B	Pathogenic	criteria provided, single submitter
1679391	NM_001374828.1(ARID1B):c.4552C>T (p.Gln1518Ter)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1685543	NM_001374828.1(ARID1B):c.2248-2A>G	ARID1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685544	NM_001374828.1(ARID1B):c.5365del (p.Ser1789fs)	ARID1B	Pathogenic	criteria provided, single submitter
1687102	NM_001374828.1(ARID1B):c.3827del (p.Glu1276fs)	ARID1B	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 16 · 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
ARID1B	Definitive	Autosomal dominant	Coffin-Siris syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARID1B	Orphanet:1465	Coffin-Siris syndrome
ARID1B	Orphanet:251056	6q25.2q25.3 microdeletion syndrome
SMARCA2	Orphanet:3051	Nicolaides-Baraitser syndrome
SMARCA2	Orphanet:637013	SMARCA2-related blepharophimosis-intellectual disability syndrome
SMARCA4	Orphanet:1465	Coffin-Siris syndrome
SMARCA4	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCA4	Orphanet:370396	Small cell carcinoma of the ovary
SMARCA4	Orphanet:466962	SMARCA4-deficient sarcoma of thorax
SMARCC2	Orphanet:1465	Coffin-Siris syndrome
ARID1A	Orphanet:1465	Coffin-Siris syndrome
SOX11	Orphanet:1465	Coffin-Siris syndrome
SOX4	Orphanet:1465	Coffin-Siris syndrome
ARID2	Orphanet:1465	Coffin-Siris syndrome
PLIN4	Orphanet:696063	PLIN4-related distal myopathy
ARSL	Orphanet:79345	Brachytelephalangic chondrodysplasia punctata
DPF2	Orphanet:1465	Coffin-Siris syndrome

Cohort genes → proteins

13 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	gencc,clinvar
SMARCA2	HGNC:11098	ENSG00000080503	P51531	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	clinvar
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	clinvar
SMARCC2	HGNC:11105	ENSG00000139613	Q8TAQ2	SWI/SNF complex subunit SMARCC2	clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
SOX11	HGNC:11191	ENSG00000176887	P35716	Transcription factor SOX-11	clinvar
SOX4	HGNC:11200	ENSG00000124766	Q06945	Transcription factor SOX-4	clinvar
ARID2	HGNC:18037	ENSG00000189079	Q68CP9	AT-rich interactive domain-containing protein 2	clinvar
PLIN4	HGNC:29393	ENSG00000167676	Q96Q06	Perilipin-4	clinvar
AIRN	HGNC:34515	ENSG00000268257		antisense of IGF2R non-protein coding RNA	clinvar
BICRA	HGNC:4332	ENSG00000063169	Q9NZM4	BRD4-interacting chromatin-remodeling complex-associated protein	clinvar
ARSL	HGNC:719	ENSG00000157399	P51690	Arylsulfatase L	clinvar
DPF2	HGNC:9964	ENSG00000133884	Q92785	Zinc finger protein ubi-d4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SMARCA2	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SMARCC2	SWI/SNF complex subunit SMARCC2	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SOX11	Transcription factor SOX-11	Transcription factor that acts as a transcriptional activator.
SOX4	Transcription factor SOX-4	Transcriptional activator that binds with high affinity to the T-cell enhancer motif 5’-AACAAAG-3’ motif.
ARID2	AT-rich interactive domain-containing protein 2	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
PLIN4	Perilipin-4	May play a role in triacylglycerol packaging into adipocytes.
BICRA	BRD4-interacting chromatin-remodeling complex-associated protein	Component of SWI/SNF chromatin remodeling subcomplex GBAF that carries out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner.
ARSL	Arylsulfatase L	Exhibits arylsulfatase activity towards the artificial substrate 4-methylumbelliferyl sulfate.
DPF2	Zinc finger protein ubi-d4	Plays an active role in transcriptional regulation by binding modified histones H3 and H4.

Protein-family classification

Druggable: 1 · Difficult: 5 · Unknown: 7 · Druggable fraction: 0.08

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	5	3.2×	0.043
Phosphatase	1	6.5×	0.217
Other/Unknown	7	1.0×	0.666

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
SMARCA2	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SMARCC2	Transcription factor	no		Chromo/chromo_shadow_dom, SANT/Myb, SWIRM
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
SOX11	Transcription factor	no		HMG_box_dom, SOX-12/11/4, HMG_box_dom_sf
SOX4	Transcription factor	no		HMG_box_dom, SOX-12/11/4, HMG_box_dom_sf
ARID2	Transcription factor	no		ARID_dom, DNA-bd_RFX, Znf_C2H2_type
PLIN4	Other/Unknown	no		Perilipin
AIRN	Other/Unknown	no
BICRA	Other/Unknown	no		GSCR1_dom, Chromatin_remod/trans_coact
ARSL	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
DPF2	Transcription factor	no		Znf_PHD, Znf_FYVE_PHD, Znf_RING/FYVE/PHD

Expression context

Cohort genes with no expression data: 0.

10 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	5
ganglionic eminence	4
bone marrow cell	3
embryo	3
secondary oocyte	3
colonic epithelium	2
calcaneal tendon	2
ventricular zone	2
oocyte	2
sural nerve	1
cervix squamous epithelium	1
pancreatic ductal cell	1
sperm	1
adipose tissue	1
hindlimb stylopod muscle	1
subcutaneous adipose tissue	1
colon	1
male germ line stem cell (sensu Vertebrata) in testis	1
diaphragm	1
body of pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
SMARCA2	301	ubiquitous	marker	calcaneal tendon, colonic epithelium, cortical plate
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
SMARCC2	299	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
SOX11	93	broad	marker	ganglionic eminence, cortical plate, embryo
SOX4	295	ubiquitous	marker	cortical plate, ganglionic eminence, embryo
ARID2	253	ubiquitous	marker	sperm, pancreatic ductal cell, secondary oocyte
PLIN4	220	broad	yes	subcutaneous adipose tissue, adipose tissue, hindlimb stylopod muscle
AIRN	65		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, colon
BICRA	267	ubiquitous	yes	oocyte, secondary oocyte, diaphragm
ARSL	174	broad	marker	body of pancreas, liver, right lobe of liver
DPF2	290	ubiquitous	marker	oocyte, secondary oocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 31.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA4	8,138
SMARCA2	4,237
SMARCC2	3,686
ARID1A	3,476
SOX4	2,846
ARID2	2,190
ARID1B	2,131
SOX11	2,090
DPF2	1,808
PLIN4	1,726

Intra-cohort edges

A	B	Sources
ARID1A	ARID1B	biogrid_interaction, string_interaction
ARID1A	ARID2	string_interaction
ARID1A	BICRA	string_interaction
ARID1A	DPF2	biogrid_interaction, string_interaction
ARID1A	SMARCA2	biogrid_interaction, string_interaction
ARID1A	SMARCA4	biogrid_interaction, intact, string_interaction
ARID1A	SMARCC2	biogrid_interaction, intact, string_interaction
ARID1A	SOX11	string_interaction
ARID1B	ARID2	string_interaction
ARID1B	BICRA	string_interaction
ARID1B	DPF2	biogrid_interaction, intact, string_interaction
ARID1B	SMARCA2	biogrid_interaction, string_interaction
ARID1B	SMARCA4	biogrid_interaction, string_interaction
ARID1B	SMARCC2	biogrid_interaction, intact, string_interaction
ARID1B	SOX11	string_interaction
ARID2	BICRA	string_interaction
ARID2	DPF2	string_interaction
ARID2	SMARCA2	string_interaction
ARID2	SMARCA4	intact, string_interaction
ARID2	SMARCC2	intact, string_interaction
BICRA	DPF2	string_interaction
BICRA	SMARCA2	string_interaction
BICRA	SMARCA4	biogrid_interaction, intact, string_interaction
DPF2	SMARCA2	biogrid_interaction, intact, string_interaction
DPF2	SMARCA4	biogrid_interaction, intact, string_interaction
DPF2	SMARCC2	biogrid_interaction, intact, string_interaction
SMARCA2	SMARCA4	string_interaction
SMARCA2	SMARCC2	intact, string_interaction
SMARCA4	SMARCC2	intact, string_interaction
SMARCA4	SOX11	string_interaction
SMARCA4	SOX4	intact

Structural data

PDB: 8 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCA2	P51531	32
SMARCA4	P51532	31
SMARCC2	Q8TAQ2	9
DPF2	Q92785	9
ARID1A	O14497	7
SOX11	P35716	4
ARID1B	Q8NFD5	2
ARID2	Q68CP9	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARSL	P51690	92.57
SOX4	Q06945	55.71
BICRA	Q9NZM4	42.79
PLIN4	Q96Q06	35.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 13 evidence-associated genes (11 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 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	6	249.2×	1e-12	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, DPF2
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	6	163.9×	9e-12	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
Regulation of MITF-M-dependent genes involved in pigmentation	6	144.9×	1e-11	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, DPF2
Formation of the canonical BAF (cBAF) complex	5	288.4×	3e-11	ARID1B, SMARCA2, SMARCA4, ARID1A, DPF2
RMTs methylate histone arginines	6	79.9×	3e-10	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
Transcriptional regulation by RUNX1	6	79.9×	3e-10	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
Regulation of endogenous retroelements	5	167.4×	3e-10	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	6	64.2×	8e-10	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, DPF2
Formation of the non-canonical BAF (ncBAF) complex	4	244.3×	5e-09	SMARCA2, SMARCA4, SMARCC2, BICRA
Formation of the polybromo-BAF (pBAF) complex	4	230.7×	6e-09	SMARCA2, SMARCA4, SMARCC2, ARID2
Chromatin organization	6	44.5×	6e-09	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
Formation of the embryonic stem cell BAF (esBAF) complex	4	218.6×	7e-09	SMARCA4, SMARCC2, ARID1A, DPF2
MITF-M-dependent gene expression	5	82.4×	7e-09	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A
Chromatin modifying enzymes	6	39.4×	9e-09	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
MITF-M-regulated melanocyte development	5	51.9×	6e-08	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A
Epigenetic regulation of gene expression	5	32.4×	6e-07	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A
RNA Polymerase II Transcription	6	12.3×	7e-06	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
Gene expression (Transcription)	6	9.7×	3e-05	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
Generic Transcription Pathway	6	8.2×	7e-05	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
Developmental Biology	5	6.6×	0.001	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A
TCF dependent signaling in response to WNT	2	21.4×	0.008	SMARCA4, SOX4
Signaling by WNT	2	20.4×	0.008	SMARCA4, SOX4
Positive Regulation of CDH1 Gene Transcription	1	86.5×	0.022	ARID1A
The activation of arylsulfatases	1	79.9×	0.023	ARSL
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	38.5×	0.045	ARSL
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	33.5×	0.050	SMARCA4
Interleukin-7 signaling	1	28.8×	0.056	SMARCA4
Glycosphingolipid metabolism	1	27.3×	0.056	ARSL
Glycosphingolipid catabolism	1	26.6×	0.056	ARSL
Deactivation of the beta-catenin transactivating complex	1	21.2×	0.068	SOX4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of G0 to G1 transition	7	429.0×	2e-16	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2, DPF2
regulation of nucleotide-excision repair	7	383.0×	3e-16	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2, DPF2
regulation of mitotic metaphase/anaphase transition	7	315.4×	8e-16	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2, DPF2
positive regulation of myoblast differentiation	7	233.1×	6e-15	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, SOX4, ARID2
positive regulation of double-strand break repair	7	218.9×	8e-15	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2, DPF2
regulation of G1/S transition of mitotic cell cycle	7	195.0×	2e-14	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2, DPF2
positive regulation of T cell differentiation	6	248.4×	5e-13	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
chromatin remodeling	8	53.1×	2e-12	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2, BICRA, DPF2
positive regulation of cell differentiation	6	145.9×	1e-11	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2
nervous system development	8	33.4×	8e-11	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, SOX11, SOX4, DPF2
positive regulation of stem cell population maintenance	5	156.3×	7e-10	SMARCA2, SMARCA4, ARID1A, BICRA, DPF2
nucleosome disassembly	4	291.8×	5e-09	SMARCA4, SMARCC2, ARID1A, ARID2
positive regulation of DNA-templated transcription	7	17.8×	2e-07	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, SOX4, BICRA
regulation of transcription by RNA polymerase II	8	8.5×	3e-06	ARID1B, SMARCA2, SMARCA4, SMARCC2, ARID1A, ARID2, BICRA, DPF2
transcription initiation-coupled chromatin remodeling	3	104.5×	2e-05	ARID1B, SMARCA4, ARID1A
negative regulation of cell differentiation	3	77.9×	4e-05	SMARCA2, SMARCA4, BICRA
noradrenergic neuron differentiation	2	437.7×	5e-05	SOX11, SOX4
neuroepithelial cell differentiation	2	278.6×	1e-04	SOX11, SOX4
sympathetic nervous system development	2	170.2×	3e-04	SOX11, SOX4
glial cell proliferation	2	161.3×	3e-04	SOX11, SOX4
camera-type eye morphogenesis	2	139.3×	4e-04	SOX11, SOX4
spinal cord development	2	92.8×	9e-04	SOX11, SOX4
negative regulation of transcription by RNA polymerase II	5	8.1×	9e-04	SMARCA2, SMARCA4, SOX11, SOX4, DPF2
positive regulation of cell population proliferation	4	12.2×	1e-03	SMARCA2, SMARCA4, SOX4, BICRA
ventricular septum morphogenesis	2	78.6×	0.001	SOX11, SOX4
negative regulation of myeloid progenitor cell differentiation	1	1532.0×	0.003	DPF2
negative regulation of transcription regulatory region DNA binding	1	1532.0×	0.003	SOX11
heterochromatin formation	2	46.4×	0.003	SMARCA2, SMARCA4
closure of optic fissure	1	766.0×	0.005	SOX11
positive regulation of lens epithelial cell proliferation	1	766.0×	0.005	SOX11

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 3 · Undrugged: 10

Druggability breadth: 6 of 13 evidence-associated genes (46%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCA2	2	2
SMARCA4	2	2
BICRA	1	2
ARID1B	0	0
SMARCC2	0	0
ARID1A	0	0
SOX11	0	0
SOX4	0	0
ARID2	0	0
PLIN4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	BICRA, SMARCA2, SMARCA4
CAMIBIRSTAT	2	SMARCA2, SMARCA4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMARCA2	311	Binding:274, Functional:25, ADMET:12
SMARCA4	230	Binding:207, ADMET:12, Functional:11
SMARCC2	7	Binding:7
ARID2	7	Binding:7
BICRA	7	Binding:7
ARID1A	6	Binding:6

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SMARCA2	311
SMARCA4	230

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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)
MOLIBRESIB	2	BICRA, SMARCA2, SMARCA4
CAMIBIRSTAT	2	SMARCA2, SMARCA4

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	3	SMARCA2, SMARCA4, BICRA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ARSL
E	Difficult family or no structure, no drug	9	ARID1B, SMARCC2, ARID1A, SOX11, SOX4, ARID2, PLIN4, AIRN, DPF2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARID1B	0	SMARCA4
SMARCC2	7	SMARCA4
ARID1A	6	SMARCA4, SMARCA2
SOX11	0	SMARCA4
ARID2	7	SMARCA4
SOX4	0	—
PLIN4	0	—
AIRN	0	—
ARSL	0	—
DPF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.