Congenital generalized lipodystrophy

Summary

Congenital generalized lipodystrophy (MONDO:0006536) is a disease (an umbrella term covering 5 Mondo subtypes) with 2 cohort genes.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital generalized lipodystrophy
Mondo ID	MONDO:0006536
EFO	EFO:1000681
OMIM	608594
DOID	DOID:0050585
SNOMED CT	284449005
UMLS	C0221032
MedGen	67438
GARD	0024436
NORD	998
Is cancer (heuristic)	no

Also known as: congenital generalised lipodystrophy (disease) · congenital generalized lipodystrophy · congenital generalized lipodystrophy (disease) · familial generalised lipodystrophy · familial generalized lipodystrophy · hereditary generalised lipodystrophy · hereditary generalized lipodystrophy · lipodystrophy, congenital generalised · lipodystrophy, congenital generalized

Data availability: 4 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lipodystrophy › hereditary lipodystrophy › congenital generalized lipodystrophy

Related subtypes (10): lipodystrophy due to peptidic growth factors deficiency, Wiedemann-Rautenstrauch syndrome, SHORT syndrome, lipodystrophy-intellectual disability-deafness syndrome, Keppen-Lubinsky syndrome, severe neurodegenerative syndrome with lipodystrophy, lipoatrophy with diabetes, leukomelanodermic papules, liver steatosis, and hypertrophic cardiomyopathy, mandibuloacral dysplasia, Berardinelli-Seip congenital lipodystrophy, familial partial lipodystrophy

Subtypes (5): congenital generalized lipodystrophy type 2, congenital generalized lipodystrophy type 1, congenital generalized lipodystrophy type 3, congenital generalized lipodystrophy type 4, lipodystrophy, congenital generalized, type 5

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

4 retrieved; paginated sample, class counts are floors:

4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1334446	NM_006412.4(AGPAT2):c.313A>G (p.Met105Val)	AGPAT2	Pathogenic	no assertion criteria provided
4848905	NM_006412.4(AGPAT2):c.176_178delinsC (p.Asn59fs)	AGPAT2	Pathogenic	criteria provided, single submitter
6625	NM_006412.4(AGPAT2):c.589-2A>G	AGPAT2	Pathogenic	criteria provided, multiple submitters, no conflicts
3063854	NM_012232.6(CAVIN1):c.141_148del (p.Asp47fs)	CAVIN1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGPAT2	Orphanet:696189	Congenital generalized lipodystrophy type 1
CAVIN1	Orphanet:228429	Congenital generalized lipodystrophy type 4

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
AGPAT2	HGNC:325	ENSG00000169692	O15120	1-acyl-sn-glycerol-3-phosphate acyltransferase beta	clinvar
CAVIN1	HGNC:9688	ENSG00000177469	Q6NZI2	Caveolae-associated protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AGPAT2	1-acyl-sn-glycerol-3-phosphate acyltransferase beta	Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone.
CAVIN1	Caveolae-associated protein 1	Plays an important role in caveolae formation and organization.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AGPAT2	Enzyme (other)	yes	2.3.1.51	Plipid/glycerol_acylTrfase, AGP_acyltrans
CAVIN1	Other/Unknown	no		Cavin_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
ileal mucosa	1
mucosa of transverse colon	1
right lobe of liver	1
popliteal artery	1
right coronary artery	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AGPAT2	257	ubiquitous	marker	mucosa of transverse colon, ileal mucosa, right lobe of liver
CAVIN1	281	ubiquitous	marker	right coronary artery, tendon of biceps brachii, popliteal artery

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAVIN1	2,304
AGPAT2	2,048

Intra-cohort edges

A	B	Sources
AGPAT2	CAVIN1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAVIN1	Q6NZI2	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGPAT2	O15120	91.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
RNA Polymerase I Transcription Termination	1	163.1×	0.030	CAVIN1
Synthesis of PA	1	146.4×	0.030	AGPAT2
RNA Polymerase I Transcription	1	142.8×	0.030	CAVIN1
RHOB GTPase cycle	1	77.2×	0.035	CAVIN1
RHOC GTPase cycle	1	73.2×	0.035	CAVIN1
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.049	AGPAT2
RHOA GTPase cycle	1	37.3×	0.049	CAVIN1
RHO GTPase cycle	1	30.1×	0.054	CAVIN1
Signaling by Rho GTPases	1	17.1×	0.076	CAVIN1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.076	CAVIN1
Neutrophil degranulation	1	11.5×	0.100	AGPAT2
Gene expression (Transcription)	1	8.9×	0.118	CAVIN1
Signal Transduction	1	5.1×	0.187	CAVIN1

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
termination of RNA polymerase I transcription	1	2808.7×	0.005	CAVIN1
transcription initiation at RNA polymerase I promoter	1	936.2×	0.005	CAVIN1
positive regulation of cytokine-mediated signaling pathway	1	842.6×	0.005	AGPAT2
CDP-diacylglycerol biosynthetic process	1	648.1×	0.005	AGPAT2
rRNA transcription	1	495.6×	0.005	CAVIN1
positive regulation of cell motility	1	383.0×	0.005	CAVIN1
triglyceride biosynthetic process	1	366.4×	0.005	AGPAT2
phosphatidic acid biosynthetic process	1	255.3×	0.006	AGPAT2
phospholipid metabolic process	1	172.0×	0.008	AGPAT2
positive regulation of cytokine production	1	135.9×	0.009	AGPAT2
protein secretion	1	131.7×	0.009	CAVIN1
epidermis development	1	105.3×	0.010	AGPAT2
response to xenobiotic stimulus	1	34.5×	0.029	AGPAT2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AGPAT2	0	0
CAVIN1	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
AGPAT2	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGPAT2	2.3.1.51	1-acylglycerol-3-phosphate O-acyltransferase

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	1	AGPAT2
E	Difficult family or no structure, no drug	1	CAVIN1

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)
AGPAT2	6	—
CAVIN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.