Coffin-Siris syndrome 11

Summary

Coffin-Siris syndrome 11 (MONDO:0032912) is a disease caused by SMARCD1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SMARCD1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Coffin-Siris syndrome 11
Mondo ID	MONDO:0032912
OMIM	618779
DOID	DOID:0112372
UMLS	C5241442
MedGen	1717402
GARD	0016379
Is cancer (heuristic)	no

Also known as: CSS11

Data availability: 22 ClinVar variants · 3 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 11

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 8, Coffin-Siris syndrome 10, 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

22 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 6 pathogenic, 1 benign, 1 likely benign, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1251964	NM_003076.5(SMARCD1):c.1432dup (p.Arg478fs)	SMARCD1	Pathogenic	no assertion criteria provided
812679	NM_003076.5(SMARCD1):c.990C>G (p.Asp330Glu)	SMARCD1	Pathogenic	no assertion criteria provided
812680	NM_003076.5(SMARCD1):c.1336A>G (p.Arg446Gly)	SMARCD1	Pathogenic	no assertion criteria provided
812681	NM_003076.5(SMARCD1):c.1457G>A (p.Trp486Ter)	SMARCD1	Pathogenic	no assertion criteria provided
812682	NM_003076.5(SMARCD1):c.1483T>C (p.Phe495Leu)	SMARCD1	Pathogenic	no assertion criteria provided
812683	NM_003076.5(SMARCD1):c.1507C>T (p.Arg503Ter)	SMARCD1	Pathogenic	criteria provided, single submitter
3765749	NM_003076.5(SMARCD1):c.1271T>C (p.Ile424Thr)	SMARCD1	Likely pathogenic	criteria provided, single submitter
1709221	NM_003076.5(SMARCD1):c.142C>G (p.Leu48Val)	LOC130007872	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805057	NM_003076.5(SMARCD1):c.107C>T (p.Pro36Leu)	LOC130007872	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342564	NM_003076.5(SMARCD1):c.566C>G (p.Thr189Ser)	SMARCD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2203774	NM_003076.5(SMARCD1):c.890T>C (p.Leu297Ser)	SMARCD1	Uncertain significance	criteria provided, single submitter
2436141	NM_003076.5(SMARCD1):c.1460C>G (p.Ala487Gly)	SMARCD1	Uncertain significance	criteria provided, single submitter
2690049	NM_003076.5(SMARCD1):c.253C>T (p.Pro85Ser)	SMARCD1	Uncertain significance	criteria provided, single submitter
3377221	NM_003076.5(SMARCD1):c.1393-1G>A	SMARCD1	Uncertain significance	criteria provided, single submitter
3383249	NM_003076.5(SMARCD1):c.1463dup (p.Glu489fs)	SMARCD1	Uncertain significance	criteria provided, single submitter
3775082	NM_003076.5(SMARCD1):c.1505GAC[1] (p.Arg503del)	SMARCD1	Uncertain significance	criteria provided, single submitter
4076187	NM_003076.5(SMARCD1):c.1072C>T (p.Pro358Ser)	SMARCD1	Uncertain significance	criteria provided, single submitter
4076188	NM_003076.5(SMARCD1):c.238G>A (p.Gly80Ser)	SMARCD1	Uncertain significance	criteria provided, single submitter
4076189	NM_003076.5(SMARCD1):c.355C>T (p.Arg119Ter)	SMARCD1	Uncertain significance	criteria provided, single submitter
1283034	NM_003076.5(SMARCD1):c.178-9C>T	SMARCD1	Benign	criteria provided, multiple submitters, no conflicts
1805271	NM_003076.5(SMARCD1):c.203G>A (p.Arg68Gln)	SMARCD1	Likely benign	criteria provided, single submitter
2642976	NM_003076.5(SMARCD1):c.336G>T (p.Gln112His)	SMARCD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
SMARCD1	Strong	Autosomal dominant	Coffin-Siris syndrome 11	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCD1	Orphanet:1465	Coffin-Siris syndrome

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
SMARCD1	HGNC:11106	ENSG00000066117	Q96GM5	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCD1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCD1	Other/Unknown	no		SWIB_MDM2_domain, SWIB_domain, SWIB_MDM2_dom_sf

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
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCD1	276	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCD1	3,208

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCD1	Q96GM5	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
Formation of the non-canonical BAF (ncBAF) complex	1	671.8×	0.008	SMARCD1
Formation of the canonical BAF (cBAF) complex	1	634.4×	0.008	SMARCD1
Formation of the polybromo-BAF (pBAF) complex	1	634.4×	0.008	SMARCD1
Formation of the embryonic stem cell BAF (esBAF) complex	1	601.0×	0.008	SMARCD1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.009	SMARCD1
Regulation of endogenous retroelements	1	368.4×	0.009	SMARCD1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.009	SMARCD1
Regulation of MITF-M-dependent genes involved in pigmentation	1	265.6×	0.009	SMARCD1
MITF-M-dependent gene expression	1	181.3×	0.012	SMARCD1
RMTs methylate histone arginines	1	146.4×	0.012	SMARCD1
Transcriptional regulation by RUNX1	1	146.4×	0.012	SMARCD1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	117.7×	0.013	SMARCD1
MITF-M-regulated melanocyte development	1	114.2×	0.013	SMARCD1
Chromatin organization	1	81.6×	0.018	SMARCD1
Chromatin modifying enzymes	1	72.3×	0.018	SMARCD1
Epigenetic regulation of gene expression	1	71.4×	0.018	SMARCD1
RNA Polymerase II Transcription	1	22.5×	0.052	SMARCD1
Gene expression (Transcription)	1	17.8×	0.062	SMARCD1
Generic Transcription Pathway	1	15.1×	0.069	SMARCD1
Developmental Biology	1	14.5×	0.069	SMARCD1

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×	0.005	SMARCD1
cellular response to fatty acid	1	702.2×	0.005	SMARCD1
regulation of G0 to G1 transition	1	674.1×	0.005	SMARCD1
regulation of nucleotide-excision repair	1	601.9×	0.005	SMARCD1
regulation of mitotic metaphase/anaphase transition	1	495.6×	0.005	SMARCD1
positive regulation of T cell differentiation	1	455.5×	0.005	SMARCD1
transcription initiation-coupled chromatin remodeling	1	383.0×	0.005	SMARCD1
positive regulation of myoblast differentiation	1	366.4×	0.005	SMARCD1
positive regulation of stem cell population maintenance	1	343.9×	0.005	SMARCD1
positive regulation of double-strand break repair	1	343.9×	0.005	SMARCD1
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.005	SMARCD1
negative regulation of cell differentiation	1	285.6×	0.005	SMARCD1
positive regulation of cell differentiation	1	267.5×	0.005	SMARCD1
chromatin remodeling	1	73.0×	0.017	SMARCD1
nervous system development	1	45.9×	0.025	SMARCD1
positive regulation of cell population proliferation	1	33.6×	0.032	SMARCD1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	SMARCD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCD1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMARCD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMARCD1	7	Binding:7

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

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	SMARCD1

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	SMARCD1
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: 0.