Aortic aneurysm, familial thoracic 12

Summary

Aortic aneurysm, familial thoracic 12 (MONDO:0030731) is a disease caused by THSD4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: THSD4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic aneurysm, familial thoracic 12
Mondo ID	MONDO:0030731
OMIM	619825
UMLS	C5676959
MedGen	1802657
GARD	0025627
Is cancer (heuristic)	no

Also known as: AAT12 · aortic aneurysm, familial thoracic 12

Data availability: 22 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial thoracic aortic aneurysm and aortic dissection › aortic aneurysm, familial thoracic 12

Related subtypes (8): aortic aneurysm, familial thoracic 4, aortic aneurysm, familial thoracic 2, aortic aneurysm, familial thoracic 6, aortic aneurysm, familial thoracic 7, aortic aneurysm, familial thoracic 8, aortic aneurysm, familial thoracic 9, aortic aneurysm, familial thoracic 10, aortic aneurysm, familial thoracic 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

22 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 4 pathogenic, 4 likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1675221	NM_024817.3(THSD4):c.740del (p.Pro246_Leu247insTer)	THSD4	Pathogenic	no assertion criteria provided
1675223	NM_024817.3(THSD4):c.1402del (p.Ala468fs)	THSD4	Pathogenic	no assertion criteria provided
1675224	NM_024817.3(THSD4):c.137_145dup (p.Asp46_Gly48dup)	THSD4	Pathogenic	no assertion criteria provided
1675225	NM_024817.3(THSD4):c.961T>A (p.Tyr321Asn)	THSD4	Pathogenic	no assertion criteria provided
2584577	Single allele	THSD4	Likely pathogenic	criteria provided, single submitter
3236718	NM_024817.3(THSD4):c.358G>T (p.Glu120Ter)	THSD4	Likely pathogenic	criteria provided, single submitter
3236719	NM_024817.3(THSD4):c.853C>T (p.Arg285Ter)	THSD4	Likely pathogenic	criteria provided, single submitter
3236720	NM_024817.3(THSD4):c.1902dup (p.Lys635fs)	THSD4	Likely pathogenic	criteria provided, single submitter
1675222	NM_024817.3(THSD4):c.2341C>T (p.Arg781Trp)	THSD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2385427	NM_024817.3(THSD4):c.2240C>T (p.Ser747Leu)	THSD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699175	NM_024817.3(THSD4):c.650A>G (p.Gln217Arg)	THSD4	Uncertain significance	criteria provided, single submitter
1699438	NM_024817.3(THSD4):c.2443C>T (p.Arg815Trp)	THSD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2320645	NM_024817.3(THSD4):c.620C>A (p.Ala207Asp)	THSD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2690233	NM_024817.3(THSD4):c.2758G>A (p.Glu920Lys)	THSD4	Uncertain significance	criteria provided, single submitter
3236721	NM_024817.3(THSD4):c.2647A>G (p.Asn883Asp)	THSD4	Uncertain significance	criteria provided, single submitter
3236722	NM_024817.3(THSD4):c.3032A>G (p.Gln1011Arg)	THSD4	Uncertain significance	criteria provided, single submitter
3242343	NM_024817.3(THSD4):c.912+1G>A	THSD4	Uncertain significance	criteria provided, single submitter
3254921	NM_024817.3(THSD4):c.2212G>A (p.Glu738Lys)	THSD4	Uncertain significance	criteria provided, single submitter
3376882	NM_024817.3(THSD4):c.2992A>C (p.Thr998Pro)	THSD4	Uncertain significance	criteria provided, single submitter
3891291	NM_024817.3(THSD4):c.2984A>C (p.Tyr995Ser)	THSD4	Uncertain significance	criteria provided, single submitter
4080542	NM_024817.3(THSD4):c.2746T>C (p.Trp916Arg)	THSD4	Uncertain significance	criteria provided, single submitter
4080543	NM_024817.3(THSD4):c.2418C>A (p.Cys806Ter)	THSD4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
THSD4	Strong	Autosomal dominant	aortic aneurysm, familial thoracic 12	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THSD4	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

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
THSD4	HGNC:25835	ENSG00000187720	Q6ZMP0	Thrombospondin type-1 domain-containing protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THSD4	Thrombospondin type-1 domain-containing protein 4	Promotes FBN1 matrix assembly.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THSD4	Other/Unknown	no		TSP1_rpt, ADAMTS_spacer1, PLAC

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
buccal mucosa cell	1
esophagus squamous epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THSD4	240	ubiquitous	marker	buccal mucosa cell, esophagus squamous epithelium, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
THSD4	1,079

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
THSD4	Q6ZMP0	67.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Defective B3GALTL causes PpS	1	308.6×	0.014	THSD4
O-glycosylation of TSR domain-containing proteins	1	300.5×	0.014	THSD4
Diseases associated with O-glycosylation of proteins	1	215.5×	0.014	THSD4
O-linked glycosylation	1	144.6×	0.014	THSD4
Diseases of glycosylation	1	131.3×	0.014	THSD4
Diseases of metabolism	1	80.4×	0.019	THSD4
Post-translational protein modification	1	19.2×	0.067	THSD4
Disease	1	13.1×	0.081	THSD4
Metabolism of proteins	1	12.4×	0.081	THSD4

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
microfibril assembly	1	16852.0×	1e-04	THSD4
elastic fiber assembly	1	1532.0×	7e-04	THSD4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
THSD4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	THSD4

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)
THSD4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.