Kleefstra syndrome 2

Summary

Kleefstra syndrome 2 (MONDO:0054701) is a disease caused by KMT2C (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: KMT2C (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 318

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Kleefstra syndrome 2
Mondo ID	MONDO:0054701
OMIM	617768
DOID	DOID:0080598
UMLS	C4540395
MedGen	1623903
GARD	0018382
Is cancer (heuristic)	no

Also known as: Kleefstra syndrome 2 · KLEFS2

Data availability: 318 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Kleefstra syndrome › Kleefstra syndrome 2

Related subtypes (2): Kleefstra syndrome due to a point mutation, Kleefstra syndrome 1

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

318 retrieved; paginated sample, class counts are floors:

177 uncertain significance, 46 conflicting classifications of pathogenicity, 33 likely pathogenic, 32 pathogenic, 9 likely benign, 8 pathogenic/likely pathogenic, 8 benign/likely benign, 3 benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1330211	GRCh37/hg19 7q36.1(chr7:150745923-152373214)x1	ABCF2	Pathogenic	criteria provided, single submitter
1342507	NC_000007.14:g.152052676_152295696del	GALNT11	Pathogenic	criteria provided, single submitter
1033181	NM_170606.3(KMT2C):c.8543del (p.Asn2848fs)	KMT2C	Pathogenic	criteria provided, multiple submitters, no conflicts
1064778	NM_170606.3(KMT2C):c.7825C>T (p.Arg2609Ter)	KMT2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299749	NM_170606.3(KMT2C):c.6938_6939del (p.Phe2313fs)	KMT2C	Pathogenic	criteria provided, single submitter
1685915	NM_170606.3(KMT2C):c.2532+1del	KMT2C	Pathogenic	criteria provided, single submitter
1699406	NM_170606.3(KMT2C):c.5419C>T (p.Gln1807Ter)	KMT2C	Pathogenic	criteria provided, single submitter
1709075	NM_170606.3(KMT2C):c.2829_2832dup (p.Val945fs)	KMT2C	Pathogenic	criteria provided, single submitter
1711190	NM_170606.3(KMT2C):c.6570_6573del (p.Phe2190fs)	KMT2C	Pathogenic	no assertion criteria provided
1727001	NM_170606.3(KMT2C):c.1759_1769del (p.Gln587fs)	KMT2C	Pathogenic	no assertion criteria provided
1806262	NM_170606.3(KMT2C):c.10724_10725dup (p.Ile3576fs)	KMT2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878498	NM_170606.3(KMT2C):c.103del (p.Arg35fs)	KMT2C	Pathogenic	criteria provided, single submitter
1992339	NM_170606.3(KMT2C):c.14006_14007del (p.Ser4669fs)	KMT2C	Pathogenic	criteria provided, single submitter
2430044	NM_170606.3(KMT2C):c.5716C>T (p.Arg1906Ter)	KMT2C	Pathogenic	criteria provided, multiple submitters, no conflicts
2572190	NM_170606.3(KMT2C):c.10266_10267del (p.Arg3423fs)	KMT2C	Pathogenic	criteria provided, single submitter
2572632	NM_170606.3(KMT2C):c.4845G>A (p.Trp1615Ter)	KMT2C	Pathogenic	criteria provided, single submitter
2576079	NM_170606.3(KMT2C):c.13597C>T (p.Arg4533Ter)	KMT2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579994	NM_170606.3(KMT2C):c.9235C>T (p.Arg3079Ter)	KMT2C	Pathogenic	criteria provided, multiple submitters, no conflicts
3234082	NM_170606.3(KMT2C):c.14068C>T (p.Arg4690Ter)	KMT2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236499	NM_170606.3(KMT2C):c.11983C>T (p.Arg3995Ter)	KMT2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3377162	NM_170606.3(KMT2C):c.4123del (p.Thr1375fs)	KMT2C	Pathogenic	criteria provided, single submitter
3896497	NM_170606.3(KMT2C):c.8420_8421del (p.Leu2806_Ser2807insTer)	KMT2C	Pathogenic	criteria provided, single submitter
3897605	NM_170606.3(KMT2C):c.4618C>T (p.Gln1540Ter)	KMT2C	Pathogenic	criteria provided, single submitter
4077048	NM_170606.3(KMT2C):c.67G>T (p.Gly23Ter)	KMT2C	Pathogenic	criteria provided, single submitter
446223	NM_170606.3(KMT2C):c.5216del (p.Pro1739fs)	KMT2C	Pathogenic	criteria provided, single submitter
446224	NM_170606.3(KMT2C):c.7550C>G (p.Ser2517Ter)	KMT2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446225	NM_170606.3(KMT2C):c.1690A>T (p.Lys564Ter)	KMT2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446226	NM_170606.3(KMT2C):c.10812_10815del (p.Lys3605fs)	KMT2C	Pathogenic	criteria provided, single submitter
4526440	NM_170606.3(KMT2C):c.12673C>T (p.Arg4225Ter)	KMT2C	Pathogenic	no assertion criteria provided
4536150	NM_170606.3(KMT2C):c.2263C>T (p.Gln755Ter)	KMT2C	Pathogenic	criteria provided, single submitter

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
KMT2C	Definitive	Autosomal dominant	Kleefstra syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KMT2C	Orphanet:261652	Kleefstra syndrome due to a point mutation

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
KMT2C	HGNC:13726	ENSG00000055609	Q8NEZ4	Histone-lysine N-methyltransferase 2C	gencc,clinvar
GALNT11	HGNC:19875	ENSG00000178234	Q8NCW6	Polypeptide N-acetylgalactosaminyltransferase 11	clinvar
ABCF2	HGNC:71	ENSG00000033050	Q9UG63	ATP-binding cassette sub-family F member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KMT2C	Histone-lysine N-methyltransferase 2C	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4).
GALNT11	Polypeptide N-acetylgalactosaminyltransferase 11	Polypeptide N-acetylgalactosaminyltransferase that catalyzes the initiation of protein O-linked glycosylation and is involved in left/right asymmetry by mediating O-glycosylation of NOTCH1.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Transporter	1	25.9×	0.114
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KMT2C	Transcription factor	no		HMGI/Y_DNA-bd_CS, SET_dom, Znf_RING
GALNT11	Enzyme (other)	yes	2.4.1.41	Ricin_B_lectin, Glyco_trans_2-like, Nucleotide-diphossugar_trans
ABCF2	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC_transporter-like_CS

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
caput epididymis	1
oocyte	1
upper arm skin	1
choroid plexus epithelium	1
nephron tubule	1
renal medulla	1
gastrocnemius	1
muscle of leg	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KMT2C	261	ubiquitous	marker	oocyte, caput epididymis, upper arm skin
GALNT11	286	ubiquitous	marker	choroid plexus epithelium, renal medulla, nephron tubule
ABCF2	259	ubiquitous	marker	sural nerve, gastrocnemius, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCF2	3,351
KMT2C	3,321
GALNT11	793

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KMT2C	Q8NEZ4	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GALNT11	Q8NCW6	85.38
ABCF2	Q9UG63	83.57

Function

Pathway analysis

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NFE2L2 regulating MDR associated enzymes	1	475.8×	0.047	ABCF2
Activation of HOX genes during differentiation	1	146.4×	0.047	KMT2C
Nuclear events mediated by NFE2L2	1	112.0×	0.047	ABCF2
Formation of WDR5-containing histone-modifying complexes	1	88.5×	0.047	KMT2C
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	71.8×	0.047	KMT2C
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	65.6×	0.047	KMT2C
O-linked glycosylation of mucins	1	61.4×	0.047	GALNT11
PKMTs methylate histone lysines	1	53.6×	0.047	KMT2C
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.047	KMT2C
Transcriptional regulation by RUNX1	1	48.8×	0.047	KMT2C
Cellular response to chemical stress	1	47.6×	0.047	ABCF2
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	40.1×	0.048	KMT2C
KEAP1-NFE2L2 pathway	1	40.1×	0.048	ABCF2
Regulation of PD-L1(CD274) transcription	1	36.2×	0.049	KMT2C
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	30.4×	0.053	KMT2C
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.053	KMT2C
Chromatin organization	1	27.2×	0.053	KMT2C
Chromatin modifying enzymes	1	24.1×	0.055	KMT2C
Epigenetic regulation of gene expression	1	23.8×	0.055	KMT2C
Cellular responses to stress	1	12.3×	0.099	ABCF2
Cellular responses to stimuli	1	10.5×	0.110	ABCF2
RNA Polymerase II Transcription	1	7.5×	0.145	KMT2C
Gene expression (Transcription)	1	6.0×	0.173	KMT2C
Generic Transcription Pathway	1	5.0×	0.193	KMT2C
Developmental Biology	1	4.8×	0.194	KMT2C

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
Notch signaling involved in heart development	1	8426.0×	0.001	GALNT11
Notch receptor processing	1	936.2×	0.005	GALNT11
regulation of Notch signaling pathway	1	421.3×	0.007	GALNT11
protein O-linked glycosylation via N-acetylgalactosamine	1	216.1×	0.010	GALNT11
determination of left/right symmetry	1	127.7×	0.013	GALNT11
protein O-linked glycosylation	1	112.3×	0.013	GALNT11
methylation	1	85.1×	0.015	KMT2C
cilium assembly	1	36.8×	0.030	GALNT11
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	KMT2C

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KMT2C	0	0
GALNT11	0	0
ABCF2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KMT2C	29	Binding:29
ABCF2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GALNT11	2.4.1.41	polypeptide N-acetylgalactosaminyltransferase

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	2	GALNT11, ABCF2
E	Difficult family or no structure, no drug	1	KMT2C

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)
KMT2C	29	—
GALNT11	0	—
ABCF2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.