van Maldergem syndrome 2

Summary

van Maldergem syndrome 2 (MONDO:0014242) is a disease caused by FAT4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: FAT4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 605

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	van Maldergem syndrome 2
Mondo ID	MONDO:0014242
OMIM	615546
DOID	DOID:0080586
UMLS	C3809875
MedGen	816205
GARD	0015984
Is cancer (heuristic)	no

Also known as: FAT4 van Maldergem syndrome · van Maldergem syndrome 2 · van Maldergem syndrome caused by mutation in FAT4 · Van Maldergem syndrome type 2 · VMLDS2

Data availability: 605 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

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

Related subtypes (1): van Maldergem 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

600 retrieved; paginated sample, class counts are floors:

490 uncertain significance, 69 conflicting classifications of pathogenicity, 16 benign, 8 likely benign, 7 likely pathogenic, 5 benign/likely benign, 4 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3589971	NM_001291303.3(FAT4):c.5704C>T (p.Arg1902Ter)	FAT4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
623344	NM_001291303.3(FAT4):c.11800+1G>T	FAT4	Pathogenic	criteria provided, single submitter
89004	NM_001291303.3(FAT4):c.12482G>T (p.Cys4161Phe)	FAT4	Pathogenic	no assertion criteria provided
89005	NM_001291303.3(FAT4):c.13199G>A (p.Cys4400Tyr)	FAT4	Pathogenic	no assertion criteria provided
89006	NM_001291303.3(FAT4):c.7123G>A (p.Glu2375Lys)	FAT4	Pathogenic	no assertion criteria provided
1710358	NM_001291303.3(FAT4):c.6982G>T (p.Glu2328Ter)	FAT4	Likely pathogenic	criteria provided, single submitter
3589912	NM_001291303.3(FAT4):c.2657del (p.Asp885_Leu886insTer)	FAT4	Likely pathogenic	criteria provided, single submitter
3589985	NM_001291303.3(FAT4):c.6457del (p.Ile2153fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3590009	NM_001291303.3(FAT4):c.7312del (p.Val2438fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3590090	NM_001291303.3(FAT4):c.11965del (p.Glu3989fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3590136	NM_001291303.3(FAT4):c.14610del (p.Lys4871fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3891868	NM_001291303.3(FAT4):c.216C>G (p.Tyr72Ter)	FAT4	Likely pathogenic	criteria provided, single submitter
1012078	NM_001291303.3(FAT4):c.11260A>G (p.Ser3754Gly)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031381	NM_001291303.3(FAT4):c.12085G>A (p.Ala4029Thr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1110181	NM_001291303.3(FAT4):c.12499G>A (p.Ala4167Thr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1112797	NM_001291303.3(FAT4):c.1244C>G (p.Pro415Arg)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1125571	NM_001291303.3(FAT4):c.3067A>G (p.Lys1023Glu)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1150708	NM_001291303.3(FAT4):c.7582G>A (p.Gly2528Arg)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1165453	NM_001291303.3(FAT4):c.9451G>A (p.Ala3151Thr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1198532	NM_001291303.3(FAT4):c.6731C>T (p.Thr2244Met)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1214983	NM_001291303.3(FAT4):c.2273C>T (p.Ala758Val)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1220268	NM_001291303.3(FAT4):c.8537G>A (p.Arg2846Gln)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1254011	NM_001291303.3(FAT4):c.14362G>A (p.Gly4788Arg)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303353	NM_001291303.3(FAT4):c.4432A>C (p.Ile1478Leu)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1307026	NM_001291303.3(FAT4):c.4228G>A (p.Val1410Met)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314680	NM_001291303.3(FAT4):c.4199G>A (p.Arg1400His)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1328875	NM_001291303.3(FAT4):c.12778G>A (p.Val4260Ile)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337703	NM_001291303.3(FAT4):c.9597T>A (p.Asp3199Glu)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1357337	NM_001291303.3(FAT4):c.3637G>T (p.Asp1213Tyr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1365452	NM_001291303.3(FAT4):c.2824A>G (p.Ile942Val)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
FAT4	Definitive	Autosomal recessive	van Maldergem syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAT4	Orphanet:2136	Hennekam syndrome
FAT4	Orphanet:314679	Cerebrofacioarticular syndrome
BCL10	Orphanet:52417	MALT lymphoma

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
FAT4	HGNC:23109	ENSG00000196159	Q6V0I7	Protocadherin Fat 4	gencc,clinvar
BCL10	HGNC:989	ENSG00000142867	O95999	B-cell lymphoma/leukemia 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAT4	Protocadherin Fat 4	Cadherins are calcium-dependent cell adhesion proteins.
BCL10	B-cell lymphoma/leukemia 10	Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAT4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
BCL10	Other/Unknown	no		CARD, DEATH-like_dom_sf, BCL10/E10

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
blood vessel layer	1
calcaneal tendon	1
cortical plate	1
esophagus squamous epithelium	1
mucosa of sigmoid colon	1
squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAT4	231	ubiquitous	marker	calcaneal tendon, cortical plate, blood vessel layer
BCL10	280	ubiquitous	marker	esophagus squamous epithelium, mucosa of sigmoid colon, squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FAT4	1,932
BCL10	1,873

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCL10	O95999	5
FAT4	Q6V0I7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Downstream signaling events of B Cell Receptor (BCR)	1	815.7×	0.010	BCL10
Protein ubiquitination	1	815.7×	0.010	BCL10
TCR signaling	1	496.5×	0.010	BCL10
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.010	BCL10
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.010	BCL10
C-type lectin receptors (CLRs)	1	237.9×	0.010	BCL10
Activation of NF-kappaB in B cells	1	196.9×	0.010	BCL10
E3 ubiquitin ligases ubiquitinate target proteins	1	193.6×	0.010	BCL10
FCERI mediated NF-kB activation	1	156.4×	0.011	BCL10
CLEC7A (Dectin-1) signaling	1	142.8×	0.011	BCL10
Downstream TCR signaling	1	128.3×	0.011	BCL10
Adaptive Immune System	1	29.8×	0.045	BCL10
Innate Immune System	1	25.5×	0.048	BCL10
Post-translational protein modification	1	19.2×	0.060	BCL10
Immune System	1	13.0×	0.081	BCL10
Metabolism of proteins	1	12.4×	0.081	BCL10

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
positive regulation of lymphotoxin A production	1	2808.7×	0.008	BCL10
negative regulation of mature B cell apoptotic process	1	2106.5×	0.008	BCL10
positive regulation of mast cell cytokine production	1	1685.2×	0.008	BCL10
quinolinate biosynthetic process	1	766.0×	0.009	BCL10
B cell apoptotic process	1	702.2×	0.009	BCL10
programmed cell death	1	648.1×	0.009	BCL10
T cell apoptotic process	1	648.1×	0.009	BCL10
antifungal innate immune response	1	468.1×	0.009	BCL10
non-canonical NF-kappaB signal transduction	1	421.3×	0.009	BCL10
positive regulation of phosphorylation	1	421.3×	0.009	BCL10
positive regulation of T cell receptor signaling pathway	1	383.0×	0.009	BCL10
hippo signaling	1	366.4×	0.009	FAT4
immunoglobulin mediated immune response	1	351.1×	0.009	BCL10
toll-like receptor signaling pathway	1	300.9×	0.010	BCL10
lipopolysaccharide-mediated signaling pathway	1	263.3×	0.010	BCL10
response to food	1	247.8×	0.010	BCL10
positive regulation of extrinsic apoptotic signaling pathway	1	227.7×	0.010	BCL10
positive regulation of T cell activation	1	221.7×	0.010	BCL10
cell-cell adhesion mediated by cadherin	1	205.5×	0.010	FAT4
heterophilic cell-cell adhesion	1	168.5×	0.012	FAT4
cellular defense response	1	159.0×	0.012	BCL10
positive regulation of interleukin-8 production	1	122.1×	0.014	BCL10
apoptotic signaling pathway	1	112.3×	0.014	BCL10
cellular response to mechanical stimulus	1	108.0×	0.014	BCL10
positive regulation of protein ubiquitination	1	106.7×	0.014	BCL10
neurogenesis	1	104.0×	0.014	FAT4
cerebral cortex development	1	102.8×	0.014	FAT4
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.014	BCL10
neural tube closure	1	93.6×	0.015	BCL10
epithelial cell differentiation	1	87.8×	0.016	FAT4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FAT4	0	0
BCL10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	FAT4, BCL10

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FAT4	0	—
BCL10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.