Cornelia de Lange syndrome 3

Summary

Cornelia de Lange syndrome 3 (MONDO:0012555) is a disease caused by SMC3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SMC3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 465

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cornelia de Lange syndrome 3
Mondo ID	MONDO:0012555
OMIM	610759
DOID	DOID:0080507
UMLS	C1853099
MedGen	339902
GARD	0015499
Is cancer (heuristic)	no

Also known as: CDLS3 · Cornelia de Lange syndrome 3 · Cornelia de Lange syndrome caused by mutation in SMC3 · Cornelia de Lange syndrome caused by mutation in Smc3 · Cornelia De Lange syndrome type 3 · SMC3 Cornelia de Lange syndrome · Smc3 Cornelia de Lange syndrome

Data availability: 465 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Cornelia de Lange syndrome › Cornelia de Lange syndrome 3

Related subtypes (5): Cornelia de Lange syndrome 1, Cornelia de Lange syndrome 2, Cornelia de Lange syndrome 5, Cornelia de Lange syndrome 4, Cornelia de Lange syndrome 6

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

465 retrieved; paginated sample, class counts are floors:

201 likely benign, 136 uncertain significance, 37 conflicting classifications of pathogenicity, 33 likely pathogenic, 27 benign, 17 pathogenic, 11 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686220	NM_005445.4(SMC3):c.2044G>A (p.Val682Ile)	SMC3	Pathogenic	criteria provided, single submitter
180199	NM_005445.4(SMC3):c.2536-5_2541del	SMC3	Pathogenic	no assertion criteria provided
208656	NM_005445.4(SMC3):c.2750A>C (p.His917Pro)	SMC3	Pathogenic	criteria provided, single submitter
209193	NM_005445.4(SMC3):c.587T>C (p.Ile196Thr)	SMC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217799	NM_005445.4(SMC3):c.139T>C (p.Phe47Leu)	SMC3	Pathogenic	no assertion criteria provided
217800	NM_005445.4(SMC3):c.703_705del (p.Thr235del)	SMC3	Pathogenic	no assertion criteria provided
217802	NM_005445.4(SMC3):c.1462G>A (p.Glu488Lys)	SMC3	Pathogenic	no assertion criteria provided
217804	NM_005445.4(SMC3):c.1997G>C (p.Gly666Ala)	SMC3	Pathogenic	no assertion criteria provided
2695095	NM_005445.4(SMC3):c.2530G>T (p.Glu844Ter)	SMC3	Pathogenic	criteria provided, single submitter
2735489	NM_005445.4(SMC3):c.1892T>C (p.Leu631Pro)	SMC3	Pathogenic	criteria provided, single submitter
2784079	NM_005445.4(SMC3):c.2899C>T (p.Arg967Ter)	SMC3	Pathogenic	criteria provided, single submitter
279893	NM_005445.4(SMC3):c.1942A>G (p.Met648Val)	SMC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3632582	NM_005445.4(SMC3):c.3454C>T (p.Gln1152Ter)	SMC3	Pathogenic	criteria provided, single submitter
3720422	NM_005445.4(SMC3):c.1127A>G (p.Tyr376Cys)	SMC3	Pathogenic	criteria provided, single submitter
4631	NM_005445.4(SMC3):c.1461AGA[1] (p.Glu488del)	SMC3	Pathogenic	no assertion criteria provided
523214	NM_005445.4(SMC3):c.1450GCT[1] (p.Ala485del)	SMC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
581922	NM_005445.4(SMC3):c.661C>T (p.Arg221Ter)	SMC3	Pathogenic	criteria provided, single submitter
626275	NM_005445.4(SMC3):c.1071_1074del (p.Glu358fs)	SMC3	Pathogenic	no assertion criteria provided
864833	NM_005445.4(SMC3):c.1138_1152del (p.Gly380_Gln384del)	SMC3	Pathogenic	no assertion criteria provided
985132	NM_005445.4(SMC3):c.3439C>G (p.Gln1147Glu)	SMC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1067573	NM_005445.4(SMC3):c.1901G>A (p.Arg634His)	SMC3	Likely pathogenic	criteria provided, single submitter
1304271	NM_005445.4(SMC3):c.1417T>G (p.Trp473Gly)	SMC3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319924	NM_005445.4(SMC3):c.3442G>T (p.Ala1148Ser)	SMC3	Likely pathogenic	no assertion criteria provided
1320235	NM_005445.4(SMC3):c.2513A>C (p.Lys838Thr)	SMC3	Likely pathogenic	criteria provided, single submitter
159970	NM_005445.4(SMC3):c.1964G>A (p.Gly655Asp)	SMC3	Likely pathogenic	criteria provided, single submitter
159976	NM_005445.4(SMC3):c.2338G>C (p.Glu780Gln)	SMC3	Likely pathogenic	criteria provided, single submitter
159990	NM_005445.4(SMC3):c.707G>C (p.Arg236Pro)	SMC3	Likely pathogenic	criteria provided, single submitter
1676567	NM_005445.4(SMC3):c.1343dup (p.Glu449fs)	SMC3	Likely pathogenic	criteria provided, single submitter
1895394	NM_005445.4(SMC3):c.2399T>C (p.Leu800Pro)	SMC3	Likely pathogenic	criteria provided, single submitter
1997640	NM_005445.4(SMC3):c.1127A>C (p.Tyr376Ser)	SMC3	Likely pathogenic	criteria provided, single submitter

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
SMC3	Definitive	Autosomal dominant	Cornelia de Lange syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMC3	Orphanet:199	Cornelia de Lange 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
SMC3	HGNC:2468	ENSG00000108055	Q9UQE7	Structural maintenance of chromosomes protein 3	gencc,clinvar
ADRA2A	HGNC:281	ENSG00000150594	P08913	Alpha-2A adrenergic receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMC3	Structural maintenance of chromosomes protein 3	Central component of cohesin, a complex required for chromosome cohesion during the cell cycle.
ADRA2A	Alpha-2A adrenergic receptor	Alpha-2 adrenergic receptors are G protein-coupled receptors for catecholamines that activate the G(i/o) protein pathway, thereby promoting adenylyl cyclase inhibition, ERK1/2 stimulation, and voltage-gated calcium channels suppression.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMC3	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
ADRA2A	GPCR	yes		GPCR_Rhodpsn, ADRA2A_rcpt, ADR_fam

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
tendon of biceps brachii	1
ventricular zone	1
cortical plate	1
endocervix	1
subcutaneous adipose tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMC3	276	ubiquitous	marker	tendon of biceps brachii, ventricular zone, oocyte
ADRA2A	234	broad	marker	cortical plate, subcutaneous adipose tissue, endocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMC3	5,056
ADRA2A	1,246

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADRA2A	P08913	19
SMC3	Q9UQE7	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 2 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
Adrenaline signalling through Alpha-2 adrenergic receptor	1	1903.3×	0.016	ADRA2A
Mitotic Telophase/Cytokinesis	1	713.8×	0.016	SMC3
Adrenoceptors	1	634.4×	0.016	ADRA2A
Cohesin Loading onto Chromatin	1	571.0×	0.016	SMC3
Establishment of Sister Chromatid Cohesion	1	519.1×	0.016	SMC3
Platelet Aggregation (Plug Formation)	1	219.6×	0.026	ADRA2A
Adrenaline,noradrenaline inhibits insulin secretion	1	196.9×	0.026	ADRA2A
Surfactant metabolism	1	184.2×	0.026	ADRA2A
Amine ligand-binding receptors	1	173.0×	0.026	ADRA2A
Meiosis	1	142.8×	0.026	SMC3
G alpha (z) signalling events	1	116.5×	0.026	ADRA2A
Regulation of insulin secretion	1	109.8×	0.026	ADRA2A
Reproduction	1	95.2×	0.026	SMC3
S Phase	1	90.6×	0.026	SMC3
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.026	SMC3
Integration of energy metabolism	1	87.8×	0.026	ADRA2A
Metabolism of proteins	2	12.4×	0.026	SMC3, ADRA2A
Signal Transduction	2	10.2×	0.026	SMC3, ADRA2A
SUMOylation	1	81.6×	0.026	SMC3
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.028	SMC3
Meiotic synapsis	1	70.5×	0.028	SMC3
ESR-mediated signaling	1	64.2×	0.029	SMC3
Platelet activation, signaling and aggregation	1	52.9×	0.032	ADRA2A
Signaling by Nuclear Receptors	1	51.0×	0.032	SMC3
Mitotic Metaphase and Anaphase	1	48.4×	0.032	SMC3
Mitotic Anaphase	1	48.4×	0.032	SMC3
Resolution of Sister Chromatid Cohesion	1	43.3×	0.035	SMC3
Estrogen-dependent gene expression	1	37.8×	0.038	SMC3
Class A/1 (Rhodopsin-like receptors)	1	37.1×	0.038	ADRA2A
Mitotic Prometaphase	1	34.6×	0.039	SMC3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of uterine smooth muscle contraction	1	8426.0×	0.004	ADRA2A
phospholipase C-activating adrenergic receptor signaling pathway	1	4213.0×	0.004	ADRA2A
establishment of meiotic sister chromatid cohesion	1	2106.5×	0.004	SMC3
thermoception	1	2106.5×	0.004	ADRA2A
negative regulation of epinephrine secretion	1	1685.2×	0.004	ADRA2A
adenylate cyclase-inhibiting adrenergic receptor signaling pathway	1	1685.2×	0.004	ADRA2A
negative regulation of norepinephrine secretion	1	1404.3×	0.004	ADRA2A
fear response	1	1404.3×	0.004	ADRA2A
establishment of mitotic sister chromatid cohesion	1	1203.7×	0.004	SMC3
positive regulation of potassium ion transport	1	1053.2×	0.004	ADRA2A
negative regulation of calcium ion-dependent exocytosis	1	936.2×	0.004	ADRA2A
adrenergic receptor signaling pathway	1	936.2×	0.004	ADRA2A
negative regulation of calcium ion transport	1	842.6×	0.004	ADRA2A
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	842.6×	0.004	ADRA2A
response to alcohol	1	766.0×	0.005	ADRA2A
response to morphine	1	601.9×	0.005	ADRA2A
intestinal absorption	1	601.9×	0.005	ADRA2A
adenylate cyclase-activating adrenergic receptor signaling pathway	1	601.9×	0.005	ADRA2A
mitotic sister chromatid cohesion	1	561.7×	0.005	SMC3
positive regulation of membrane protein ectodomain proteolysis	1	468.1×	0.006	ADRA2A
negative regulation of lipid catabolic process	1	421.3×	0.006	ADRA2A
regulation of vasoconstriction	1	401.2×	0.006	ADRA2A
sister chromatid cohesion	1	383.0×	0.006	SMC3
positive regulation of wound healing	1	263.3×	0.008	ADRA2A
positive regulation of epidermal growth factor receptor signaling pathway	1	247.8×	0.008	ADRA2A
negative regulation of insulin secretion	1	247.8×	0.008	ADRA2A
presynaptic modulation of chemical synaptic transmission	1	227.7×	0.008	ADRA2A
stem cell population maintenance	1	210.7×	0.009	SMC3
cellular response to hormone stimulus	1	191.5×	0.009	ADRA2A
regulation of DNA replication	1	183.2×	0.009	SMC3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ADRA2A	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADRA2A	418	4
SMC3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	ADRA2A
TELMISARTAN	4	ADRA2A
BEXAROTENE	4	ADRA2A
CLOTRIMAZOLE	4	ADRA2A
METHYSERGIDE	4	ADRA2A
TIZANIDINE	4	ADRA2A
ACETOPHENAZINE	4	ADRA2A
MESORIDAZINE	4	ADRA2A
PHENELZINE	4	ADRA2A
EPINASTINE	4	ADRA2A
DROPERIDOL	4	ADRA2A
ARIPIPRAZOLE	4	ADRA2A
AMOXAPINE	4	ADRA2A
NORETHINDRONE	4	ADRA2A
DESLORATADINE	4	ADRA2A
TETRABENAZINE	4	ADRA2A
PALONOSETRON	4	ADRA2A
DIETHYLPROPION	4	ADRA2A
TIZANIDINE HYDROCHLORIDE	4	ADRA2A
DIMENHYDRINATE	4	ADRA2A
NEFAZODONE HYDROCHLORIDE	4	ADRA2A
GUANFACINE HYDROCHLORIDE	4	ADRA2A
DIHYDROERGOTAMINE MESYLATE	4	ADRA2A
OXYMETAZOLINE HYDROCHLORIDE	4	ADRA2A
AZELASTINE HYDROCHLORIDE	4	ADRA2A
THIOTHIXENE	4	ADRA2A
BENZTHIAZIDE	4	ADRA2A
CABERGOLINE	4	ADRA2A
SERTACONAZOLE	4	ADRA2A
BENZTROPINE	4	ADRA2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ADRA2A	896	Binding:687, Functional:190, ADMET:17, Unclassified:2
SMC3	7	Binding:7

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ADRA2A	896

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

30 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)
CANDESARTAN CILEXETIL	4	ADRA2A
TELMISARTAN	4	ADRA2A
BEXAROTENE	4	ADRA2A
CLOTRIMAZOLE	4	ADRA2A
METHYSERGIDE	4	ADRA2A
TIZANIDINE	4	ADRA2A
ACETOPHENAZINE	4	ADRA2A
MESORIDAZINE	4	ADRA2A
PHENELZINE	4	ADRA2A
EPINASTINE	4	ADRA2A
DROPERIDOL	4	ADRA2A
ARIPIPRAZOLE	4	ADRA2A
AMOXAPINE	4	ADRA2A
NORETHINDRONE	4	ADRA2A
DESLORATADINE	4	ADRA2A
TETRABENAZINE	4	ADRA2A
PALONOSETRON	4	ADRA2A
DIETHYLPROPION	4	ADRA2A
TIZANIDINE HYDROCHLORIDE	4	ADRA2A
DIMENHYDRINATE	4	ADRA2A
NEFAZODONE HYDROCHLORIDE	4	ADRA2A
GUANFACINE HYDROCHLORIDE	4	ADRA2A
DIHYDROERGOTAMINE MESYLATE	4	ADRA2A
OXYMETAZOLINE HYDROCHLORIDE	4	ADRA2A
AZELASTINE HYDROCHLORIDE	4	ADRA2A
THIOTHIXENE	4	ADRA2A
BENZTHIAZIDE	4	ADRA2A
CABERGOLINE	4	ADRA2A
SERTACONAZOLE	4	ADRA2A
BENZTROPINE	4	ADRA2A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ADRA2A
B	Phased (≥1) drug, not yet approved	1	SMC3
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.