Coffin-Siris syndrome 8

Summary

Coffin-Siris syndrome 8 (MONDO:0032702) is a disease caused by SMARCC2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SMARCC2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 83

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Coffin-Siris syndrome 8
Mondo ID	MONDO:0032702
OMIM	618362
DOID	DOID:0112367
UMLS	C5193054
MedGen	1679527
GARD	0016347
Is cancer (heuristic)	no

Also known as: CSS8 · SMARCC2-related BAFopathy

Data availability: 83 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Coffin-Siris syndrome › Coffin-Siris syndrome 8

Related subtypes (10): Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, Coffin-Siris syndrome 5, Coffin-Siris syndrome 12, Coffin-Siris syndrome 10, Coffin-Siris syndrome 11, Coffin-Siris syndrome 7

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

83 retrieved; paginated sample, class counts are floors:

45 uncertain significance, 15 likely pathogenic, 11 pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4280325	NC_000012.12:g.56173943_56407078inv	ANKRD52	Pathogenic	criteria provided, single submitter
1219096	NM_001330288.2(SMARCC2):c.805C>T (p.Arg269Ter)	SMARCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1302011	NM_001330288.2(SMARCC2):c.574C>T (p.Arg192Ter)	SMARCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722383	NM_001330288.2(SMARCC2):c.3381_3388del (p.Ile1128fs)	SMARCC2	Pathogenic	criteria provided, single submitter
1992356	NM_001330288.2(SMARCC2):c.1094_1097del (p.Lys365fs)	SMARCC2	Pathogenic	criteria provided, single submitter
2506488	NM_001330288.2(SMARCC2):c.1091del (p.Lys364fs)	SMARCC2	Pathogenic	criteria provided, single submitter
3342316	NM_001330288.2(SMARCC2):c.1420C>T (p.Arg474Ter)	SMARCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381186	NM_001330288.2(SMARCC2):c.1496+1G>T	SMARCC2	Pathogenic	criteria provided, single submitter
4072348	NM_001330288.2(SMARCC2):c.1101dup (p.Glu368fs)	SMARCC2	Pathogenic	criteria provided, single submitter
623247	NM_001330288.2(SMARCC2):c.1926+2T>C	SMARCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
623248	NM_001330288.2(SMARCC2):c.1311-3C>G	SMARCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
623249	NM_001330288.2(SMARCC2):c.1922T>C (p.Leu641Pro)	SMARCC2	Pathogenic	criteria provided, single submitter
623250	NM_001330288.2(SMARCC2):c.723G>A (p.Trp241Ter)	SMARCC2	Pathogenic	no assertion criteria provided
623251	NM_001330288.2(SMARCC2):c.2779A>G (p.Met927Val)	SMARCC2	Pathogenic	no assertion criteria provided
931991	NM_001330288.2(SMARCC2):c.1926+1G>A	SMARCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1029506	NM_001330288.2(SMARCC2):c.1310+1G>T	SMARCC2	Likely pathogenic	criteria provided, single submitter
2429193	NM_001330288.2(SMARCC2):c.1497-2A>G	SMARCC2	Likely pathogenic	criteria provided, single submitter
2431773	NM_001330288.2(SMARCC2):c.1496+2T>G	SMARCC2	Likely pathogenic	criteria provided, single submitter
2442001	NM_001330288.2(SMARCC2):c.1396C>T (p.Arg466Ter)	SMARCC2	Likely pathogenic	criteria provided, single submitter
3764680	NM_001330288.2(SMARCC2):c.2538_2548+1del	SMARCC2	Likely pathogenic	criteria provided, single submitter
3772690	NM_001330288.2(SMARCC2):c.2186-3C>G	SMARCC2	Likely pathogenic	criteria provided, single submitter
3775160	NM_001330288.2(SMARCC2):c.1341del (p.Glu448fs)	SMARCC2	Likely pathogenic	criteria provided, single submitter
3775449	NM_001330288.2(SMARCC2):c.397C>T (p.Gln133Ter)	SMARCC2	Likely pathogenic	criteria provided, single submitter
3899280	NM_001330288.2(SMARCC2):c.80_83del (p.Val27fs)	SMARCC2	Likely pathogenic	criteria provided, single submitter
4077049	NM_001330288.2(SMARCC2):c.2791G>A (p.Glu931Lys)	SMARCC2	Likely pathogenic	criteria provided, single submitter
4281616	NM_001330288.2(SMARCC2):c.2404G>T (p.Glu802Ter)	SMARCC2	Likely pathogenic	criteria provided, single submitter
4537466	NM_001330288.2(SMARCC2):c.2746A>G (p.Lys916Glu)	SMARCC2	Likely pathogenic	criteria provided, single submitter
807690	NM_001330288.2(SMARCC2):c.385A>G (p.Lys129Glu)	SMARCC2	Likely pathogenic	criteria provided, single submitter
931614	NM_001330288.2(SMARCC2):c.3221dup (p.Gly1075fs)	SMARCC2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
976148	NM_001330288.2(SMARCC2):c.2771A>G (p.Glu924Gly)	SMARCC2	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SMARCC2	Definitive	Autosomal dominant	Coffin-Siris syndrome 8	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCC2	Orphanet:1465	Coffin-Siris syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCC2	HGNC:11105	ENSG00000139613	Q8TAQ2	SWI/SNF complex subunit SMARCC2	gencc,clinvar
ANKRD52	HGNC:26614	ENSG00000139645	Q8NB46	Serine/threonine-protein phosphatase 6 regulatory ankyrin repeat subunit C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCC2	SWI/SNF complex subunit SMARCC2	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
ANKRD52	Serine/threonine-protein phosphatase 6 regulatory ankyrin repeat subunit C	Putative regulatory subunit of protein phosphatase 6 (PP6) that may be involved in the recognition of phosphoprotein substrates.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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
Scaffold/PPI	1	8.6×	0.225
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCC2	Transcription factor	no		Chromo/chromo_shadow_dom, SANT/Myb, SWIRM
ANKRD52	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Dendritic_Spine_Reg/Scaffold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
ventricular zone	1
lateral nuclear group of thalamus	1
right adrenal gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCC2	299	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate
ANKRD52	191	ubiquitous	yes	stromal cell of endometrium, lateral nuclear group of thalamus, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCC2	3,686
ANKRD52	2,159

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCC2	Q8TAQ2	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD52	Q8NB46	85.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the non-canonical BAF (ncBAF) complex	1	671.8×	0.010	SMARCC2
Formation of the polybromo-BAF (pBAF) complex	1	634.4×	0.010	SMARCC2
Formation of the embryonic stem cell BAF (esBAF) complex	1	601.0×	0.010	SMARCC2
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.010	SMARCC2
Regulation of endogenous retroelements	1	368.4×	0.010	SMARCC2
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.010	SMARCC2
Regulation of MITF-M-dependent genes involved in pigmentation	1	265.6×	0.010	SMARCC2
MITF-M-dependent gene expression	1	181.3×	0.013	SMARCC2
RMTs methylate histone arginines	1	146.4×	0.013	SMARCC2
Transcriptional regulation by RUNX1	1	146.4×	0.013	SMARCC2
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	117.7×	0.014	SMARCC2
MITF-M-regulated melanocyte development	1	114.2×	0.014	SMARCC2
Chromatin organization	1	81.6×	0.018	SMARCC2
Chromatin modifying enzymes	1	72.3×	0.018	SMARCC2
Epigenetic regulation of gene expression	1	71.4×	0.018	SMARCC2
RNA Polymerase II Transcription	1	22.5×	0.053	SMARCC2
Gene expression (Transcription)	1	17.8×	0.063	SMARCC2
Generic Transcription Pathway	1	15.1×	0.069	SMARCC2
Developmental Biology	1	14.5×	0.069	SMARCC2

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
nucleosome disassembly	1	802.5×	0.006	SMARCC2
regulation of G0 to G1 transition	1	674.1×	0.006	SMARCC2
regulation of nucleotide-excision repair	1	601.9×	0.006	SMARCC2
regulation of mitotic metaphase/anaphase transition	1	495.6×	0.006	SMARCC2
positive regulation of T cell differentiation	1	455.5×	0.006	SMARCC2
positive regulation of myoblast differentiation	1	366.4×	0.006	SMARCC2
positive regulation of double-strand break repair	1	343.9×	0.006	SMARCC2
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.006	SMARCC2
positive regulation of cell differentiation	1	267.5×	0.006	SMARCC2
chromatin remodeling	1	73.0×	0.019	SMARCC2
nervous system development	1	45.9×	0.028	SMARCC2
negative regulation of DNA-templated transcription	1	31.6×	0.037	SMARCC2
positive regulation of DNA-templated transcription	1	27.9×	0.039	SMARCC2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	SMARCC2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANKRD52	1	2
SMARCC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ANKRD52

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMARCC2	7	Binding:7
ANKRD52	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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	ANKRD52

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	1	ANKRD52
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SMARCC2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMARCC2	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.