Coffin-Siris syndrome 6

Summary

Coffin-Siris syndrome 6 (MONDO:0033492) is a disease caused by ARID2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: ARID2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 124

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Coffin-Siris syndrome 6
Mondo ID	MONDO:0033492
OMIM	617808
DOID	DOID:0080297
UMLS	C4540499
MedGen	1615540
GARD	0016254
Is cancer (heuristic)	no

Also known as: ARID2-related BAFopathy · Coffin-Siris syndrome 6 · CSS6

Data availability: 124 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal dominant non-syndromic intellectual disability › Coffin-Siris syndrome 6

Related subtypes (25): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 34, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

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

124 retrieved; paginated sample, class counts are floors:

44 pathogenic, 43 uncertain significance, 23 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 likely benign, 2 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3390356	GRCh38/hg38 12q12-13.11(chr12:45299856-46290196)x1	ANO6	Pathogenic	no assertion criteria provided
1031208	NM_152641.4(ARID2):c.820C>T (p.Arg274Ter)	ARID2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034327	NM_152641.4(ARID2):c.5026C>T (p.Gln1676Ter)	ARID2	Pathogenic	criteria provided, single submitter
1170954	NM_152641.4(ARID2):c.118dup (p.Val40fs)	ARID2	Pathogenic	criteria provided, single submitter
1170955	NM_152641.4(ARID2):c.400dup (p.Gln134fs)	ARID2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1170956	NM_152641.4(ARID2):c.2401_2402del (p.Met801fs)	ARID2	Pathogenic	criteria provided, single submitter
1170957	NM_152641.4(ARID2):c.3301_3302insAGGT (p.Val1101fs)	ARID2	Pathogenic	criteria provided, single submitter
1170958	NM_152641.4(ARID2):c.3814C>T (p.Arg1272Ter)	ARID2	Pathogenic	criteria provided, multiple submitters, no conflicts
1170959	NM_152641.4(ARID2):c.4732C>T (p.Gln1578Ter)	ARID2	Pathogenic	criteria provided, single submitter
1170960	NM_152641.3:c.(705+1_706-1)_(1330+1_1331-1)del	ARID2	Pathogenic	no assertion criteria provided
1170961	GRCh37/hg19 12q12(chr12:46168172-46304719)x1	ARID2	Pathogenic	no assertion criteria provided
1170962	GRCh37/hg19 12q12(chr12:46150008-46321670)x1	ARID2	Pathogenic	no assertion criteria provided
1285520	NM_152641.4(ARID2):c.4540_4541delinsGAA (p.Thr1514fs)	ARID2	Pathogenic	criteria provided, single submitter
1343246	NM_152641.4(ARID2):c.1331-1G>C	ARID2	Pathogenic	criteria provided, single submitter
1526286	NC_000012.12:g.45690000_45750000del	ARID2	Pathogenic	no assertion criteria provided
1679288	NM_152641.4(ARID2):c.4210dup (p.Gln1404fs)	ARID2	Pathogenic	criteria provided, single submitter
1684625	NM_152641.4(ARID2):c.2377C>T (p.Gln793Ter)	ARID2	Pathogenic	no assertion criteria provided
1699019	NM_152641.4(ARID2):c.4255_4256del (p.Pro1419fs)	ARID2	Pathogenic	criteria provided, single submitter
1710278	NM_152641.4(ARID2):c.675G>A (p.Trp225Ter)	ARID2	Pathogenic	no assertion criteria provided
1710463	NM_152641.4(ARID2):c.2767C>T (p.Gln923Ter)	ARID2	Pathogenic	criteria provided, single submitter
1805865	NM_152641.4(ARID2):c.1334_1338del (p.Met445fs)	ARID2	Pathogenic	criteria provided, single submitter
207823	NM_152641.4(ARID2):c.2536del (p.Val846fs)	ARID2	Pathogenic	criteria provided, single submitter
2691005	NM_152641.4(ARID2):c.869_881del (p.Ala290fs)	ARID2	Pathogenic	criteria provided, single submitter
3024465	NM_152641.4(ARID2):c.836_839dup (p.Asp280fs)	ARID2	Pathogenic	criteria provided, single submitter
3024471	NM_152641.4(ARID2):c.1261dup (p.Val421fs)	ARID2	Pathogenic	criteria provided, single submitter
3024472	NM_152641.4(ARID2):c.1556_1559del (p.Asp519fs)	ARID2	Pathogenic	criteria provided, single submitter
3024473	NM_152641.4(ARID2):c.2441_2442del (p.Thr814fs)	ARID2	Pathogenic	criteria provided, single submitter
3024475	NM_152641.4(ARID2):c.3654dup (p.Ala1219fs)	ARID2	Pathogenic	criteria provided, single submitter
3024476	NM_152641.4(ARID2):c.4021_4027del (p.Ser1341fs)	ARID2	Pathogenic	criteria provided, single submitter
3024477	NM_152641.4(ARID2):c.4607_4610del (p.Val1536fs)	ARID2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
ARID2	Strong	Autosomal dominant	Coffin-Siris syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARID2	Orphanet:1465	Coffin-Siris syndrome
ANO6	Orphanet:806	Scott syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARID2	HGNC:18037	ENSG00000189079	Q68CP9	AT-rich interactive domain-containing protein 2	gencc,clinvar
ANO6	HGNC:25240	ENSG00000177119	Q4KMQ2	Anoctamin-6	clinvar
GIGYF1	HGNC:9126	ENSG00000146830	O75420	GRB10-interacting GYF protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
ANO6	Anoctamin-6	Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets and osteoblasts.
GIGYF1	GRB10-interacting GYF protein 1	May act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARID2	Transcription factor	no		ARID_dom, DNA-bd_RFX, Znf_C2H2_type
ANO6	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
GIGYF1	Other/Unknown	no		GYF, GYF-like_dom_sf, GRB10-interact_GYF

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	2
pancreatic ductal cell	1
sperm	1
epithelial cell of pancreas	1
tibialis anterior	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARID2	253	ubiquitous	marker	sperm, pancreatic ductal cell, secondary oocyte
ANO6	254	ubiquitous	marker	epithelial cell of pancreas, secondary oocyte, tibialis anterior
GIGYF1	242	ubiquitous	marker	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARID2	2,190
GIGYF1	1,653
ANO6	1,218

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARID2	Q68CP9	2
GIGYF1	O75420	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANO6	Q4KMQ2	82.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ANO6 does not expose PS, PE on the platelet membrane	1	5710.0×	0.004	ANO6
Induction of Cell-Cell Fusion	1	439.2×	0.020	ANO6
Amplification and propagation of coagulation cascade	1	317.2×	0.020	ANO6
Formation of the polybromo-BAF (pBAF) complex	1	317.2×	0.020	ARID2
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	150.3×	0.028	ARID2
Late SARS-CoV-2 Infection Events	1	146.4×	0.028	ANO6
Regulation of clotting cascade	1	116.5×	0.031	ANO6
RMTs methylate histone arginines	1	73.2×	0.037	ARID2
Transcriptional regulation by RUNX1	1	73.2×	0.037	ARID2
Stimuli-sensing channels	1	68.0×	0.037	ANO6
Ion channel transport	1	48.0×	0.047	ANO6
Chromatin organization	1	40.8×	0.048	ARID2
SARS-CoV-2 Infection	1	40.2×	0.048	ANO6
Chromatin modifying enzymes	1	36.1×	0.049	ARID2
SARS-CoV Infections	1	27.7×	0.060	ANO6
Viral Infection Pathways	1	15.4×	0.100	ANO6
Innate Immune System	1	12.8×	0.103	ANO6
Transport of small molecules	1	12.6×	0.103	ANO6
Infectious disease	1	12.4×	0.103	ANO6
Neutrophil degranulation	1	11.5×	0.103	ANO6
RNA Polymerase II Transcription	1	11.3×	0.103	ARID2
Gene expression (Transcription)	1	8.9×	0.124	ARID2
Generic Transcription Pathway	1	7.5×	0.139	ARID2
Disease	1	6.5×	0.148	ANO6
Immune System	1	6.5×	0.148	ANO6

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phosphatidylserine exposure on blood platelet	1	5617.3×	0.004	ANO6
positive regulation of monoatomic ion transmembrane transport	1	2808.7×	0.004	ANO6
activation of blood coagulation via clotting cascade	1	1872.4×	0.004	ANO6
positive regulation of potassium ion export across plasma membrane	1	1872.4×	0.004	ANO6
purinergic nucleotide receptor signaling pathway	1	1404.3×	0.004	ANO6
calcium activated phosphatidylserine scrambling	1	1404.3×	0.004	ANO6
negative regulation of cell volume	1	1123.5×	0.004	ANO6
calcium activated phosphatidylcholine scrambling	1	1123.5×	0.004	ANO6
pore complex assembly	1	624.1×	0.006	ANO6
coronary artery morphogenesis	1	624.1×	0.006	ARID2
homeostatic process	1	561.7×	0.006	ARID2
plasma membrane phospholipid scrambling	1	510.7×	0.006	ANO6
bleb assembly	1	510.7×	0.006	ANO6
positive regulation of phagocytosis, engulfment	1	432.1×	0.007	ANO6
nucleosome disassembly	1	267.5×	0.009	ARID2
positive regulation of monocyte chemotaxis	1	267.5×	0.009	ANO6
regulation of G0 to G1 transition	1	224.7×	0.010	ARID2
regulation of nucleotide-excision repair	1	200.6×	0.011	ARID2
cardiac muscle cell proliferation	1	193.7×	0.011	ARID2
regulation of mitotic metaphase/anaphase transition	1	165.2×	0.011	ARID2
insulin-like growth factor receptor signaling pathway	1	165.2×	0.011	GIGYF1
embryonic organ development	1	160.5×	0.011	ARID2
positive regulation of T cell differentiation	1	151.8×	0.011	ARID2
positive regulation of bone mineralization	1	130.6×	0.012	ANO6
positive regulation of double-strand break repair via homologous recombination	1	127.7×	0.012	ARID2
heart morphogenesis	1	124.8×	0.012	ARID2
positive regulation of myoblast differentiation	1	122.1×	0.012	ARID2
positive regulation of double-strand break repair	1	114.6×	0.012	ARID2
regulation of G1/S transition of mitotic cell cycle	1	102.1×	0.013	ARID2
positive regulation of cell differentiation	1	89.2×	0.015	ARID2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARID2	0	0
ANO6	0	0
GIGYF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ARID2	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	ARID2, ANO6, GIGYF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARID2	7	—
ANO6	0	—
GIGYF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.