Congenital generalized lipodystrophy type 1

Summary

Congenital generalized lipodystrophy type 1 (MONDO:0012071) is a disease caused by AGPAT2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: AGPAT2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 179

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital generalized lipodystrophy type 1
Mondo ID	MONDO:0012071
OMIM	608594
Orphanet	696189
DOID	DOID:0111135
UMLS	C1720862
MedGen	318592
GARD	0000084
Is cancer (heuristic)	no

Also known as: AGPAT2 congenital generalised lipodystrophy (disease) · AGPAT2 congenital generalized lipodystrophy (disease) · AGPAT2-related Brunzell syndrome · Berardinelli-Seip congenital lipodystrophy type 1 · Berardinelli-Seip congenital lipodystrophy, type 1 · BSCL1 · CGL1 · congenital generalised lipodystrophy (disease) caused by mutation in AGPAT2 · congenital generalized lipodystrophy (disease) caused by mutation in AGPAT2 · congenital generalized lipodystrophy type 1 · lipodystrophy, congenital generalized, type 1

Data availability: 179 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lipodystrophy › hereditary lipodystrophy › congenital generalized lipodystrophy › congenital generalized lipodystrophy type 1

Related subtypes (4): congenital generalized lipodystrophy type 2, 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

179 retrieved; paginated sample, class counts are floors:

89 uncertain significance, 21 conflicting classifications of pathogenicity, 16 pathogenic, 11 benign, 11 benign/likely benign, 8 likely pathogenic, 8 likely benign, 8 not provided, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072415	NM_006412.4(AGPAT2):c.369_372del (p.Leu124fs)	AGPAT2	Pathogenic	criteria provided, multiple submitters, no conflicts
1687558	NM_006412.4(AGPAT2):c.38T>A (p.Leu13Ter)	AGPAT2	Pathogenic	criteria provided, single submitter
210104	NM_006412.4(AGPAT2):c.406G>A (p.Gly136Arg)	AGPAT2	Pathogenic	criteria provided, single submitter
2506961	NM_006412.4(AGPAT2):c.316+1G>T	AGPAT2	Pathogenic	no assertion criteria provided
3256879	NM_006412.4(AGPAT2):c.530_537dup (p.Asp180fs)	AGPAT2	Pathogenic	criteria provided, single submitter
365922	NM_006412.4(AGPAT2):c.646A>T (p.Lys216Ter)	AGPAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372105	NM_006412.4(AGPAT2):c.299G>A (p.Ser100Asn)	AGPAT2	Pathogenic	criteria provided, single submitter
372106	NM_006412.4(AGPAT2):c.492+1G>A	AGPAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372107	NM_006412.3(AGPAT2):c.(316+1_317-1)_(588+1_589-1)del (p.Leu107AlafsTer279)	AGPAT2	Pathogenic	no assertion criteria provided
372108	NM_006412.4(AGPAT2):c.514G>A (p.Glu172Lys)	AGPAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374338	NM_006412.4(AGPAT2):c.503G>A (p.Trp168Ter)	AGPAT2	Pathogenic	no assertion criteria provided
430117	NM_006412.4(AGPAT2):c.662-2A>C	AGPAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549711	NM_006412.4(AGPAT2):c.513del (p.Glu172fs)	AGPAT2	Pathogenic	no assertion criteria provided
549712	NM_006412.4(AGPAT2):c.622_626del (p.Ser208fs)	AGPAT2	Pathogenic	no assertion criteria provided
6624	NM_006412.4(AGPAT2):c.202C>T (p.Arg68Ter)	AGPAT2	Pathogenic	criteria provided, multiple submitters, no conflicts
6625	NM_006412.4(AGPAT2):c.589-2A>G	AGPAT2	Pathogenic	criteria provided, multiple submitters, no conflicts
6626	NM_006412.4(AGPAT2):c.377dup (p.Pro128fs)	AGPAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6627	NM_006412.4(AGPAT2):c.683T>C (p.Leu228Pro)	AGPAT2	Pathogenic	no assertion criteria provided
6629	NM_006412.4(AGPAT2):c.643A>T (p.Lys215Ter)	AGPAT2	Pathogenic	no assertion criteria provided
6630	NM_006412.4(AGPAT2):c.493-1G>C	AGPAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6631	NM_006412.4(AGPAT2):c.570C>A (p.Tyr190Ter)	AGPAT2	Pathogenic	no assertion criteria provided
6632	NM_006412.4(AGPAT2):c.366_588+534del	AGPAT2	Pathogenic	no assertion criteria provided
800897	NM_006412.4(AGPAT2):c.335del (p.Pro112fs)	AGPAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285417	NM_006412.4(AGPAT2):c.685G>T (p.Glu229Ter)	AGPAT2	Likely pathogenic	criteria provided, single submitter
1806161	NM_006412.4(AGPAT2):c.493-2A>G	AGPAT2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065518	NM_006412.4(AGPAT2):c.158del (p.Gly53fs)	AGPAT2	Likely pathogenic	criteria provided, single submitter
3234919	NM_006412.4(AGPAT2):c.254_258dup (p.Gln87fs)	AGPAT2	Likely pathogenic	criteria provided, single submitter
3596810	NM_006412.4(AGPAT2):c.769del (p.Leu257fs)	AGPAT2	Likely pathogenic	criteria provided, single submitter
3596834	NM_006412.4(AGPAT2):c.242_245del (p.Arg81fs)	AGPAT2	Likely pathogenic	criteria provided, single submitter
3596844	NM_006412.4(AGPAT2):c.34del (p.Leu12fs)	AGPAT2	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
AGPAT2	Definitive	Autosomal recessive	congenital generalized lipodystrophy type 1	5

Orphanet rare-disease linkage (cohort genes)

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

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
AGPAT2	HGNC:325	ENSG00000169692	O15120	1-acyl-sn-glycerol-3-phosphate acyltransferase beta	gencc,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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AGPAT2	Enzyme (other)	yes	2.3.1.51	Plipid/glycerol_acylTrfase, AGP_acyltrans

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
ileal mucosa	1
mucosa of transverse colon	1
right lobe of liver	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGPAT2	2,048

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGPAT2	O15120	91.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Synthesis of PA	1	292.8×	0.010	AGPAT2
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.018	AGPAT2
Neutrophil degranulation	1	23.1×	0.043	AGPAT2

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
positive regulation of cytokine-mediated signaling pathway	1	1685.2×	0.003	AGPAT2
CDP-diacylglycerol biosynthetic process	1	1296.3×	0.003	AGPAT2
triglyceride biosynthetic process	1	732.7×	0.004	AGPAT2
phosphatidic acid biosynthetic process	1	510.7×	0.004	AGPAT2
phospholipid metabolic process	1	343.9×	0.005	AGPAT2
positive regulation of cytokine production	1	271.8×	0.005	AGPAT2
epidermis development	1	210.7×	0.005	AGPAT2
response to xenobiotic stimulus	1	69.1×	0.014	AGPAT2

Therapeutics

Drug target analysis

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

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
AGPAT2	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: 1; 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	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AGPAT2	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.