Arterial calcification, generalized, of infancy, 2

Summary

Arterial calcification, generalized, of infancy, 2 (MONDO:0013768) is a disease caused by ABCC6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ABCC6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 500

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arterial calcification, generalized, of infancy, 2
Mondo ID	MONDO:0013768
OMIM	614473
UMLS	C3276161
MedGen	477791
GARD	0024947
Is cancer (heuristic)	no

Also known as: ABCC6 arterial calcification of infancy · arterial calcification of infancy caused by mutation in ABCC6 · arterial calcification, generalized, of infancy, 2 · arterial calcification, generalized, of infancy, type 2 · GACI2

Data availability: 500 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › arterial calcification of infancy › arterial calcification, generalized, of infancy, 2

Related subtypes (1): arterial calcification, generalized, of infancy, 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

500 retrieved; paginated sample, class counts are floors:

258 uncertain significance, 57 conflicting classifications of pathogenicity, 45 benign, 39 likely benign, 32 pathogenic/likely pathogenic, 27 benign/likely benign, 27 pathogenic, 15 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067354	NM_001171.6(ABCC6):c.1255C>T (p.Arg419Trp)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179156	GRCh37/hg19 16p13.11(chr16:16248464-16259810)	ABCC6	Pathogenic	no assertion criteria provided
1456552	NM_001171.6(ABCC6):c.3887G>A (p.Gly1296Asp)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457838	NM_001171.6(ABCC6):c.3987dup (p.Ile1330fs)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2420625	NM_001171.6(ABCC6):c.3510G>A (p.Trp1170Ter)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265018	NM_001171.6(ABCC6):c.1553G>A (p.Arg518Gln)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265021	NM_001171.6(ABCC6):c.4016G>A (p.Arg1339His)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30337	NM_001171.6(ABCC6):c.2294G>A (p.Arg765Gln)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
30338	NM_001171.6(ABCC6):c.4216C>A (p.Gln1406Lys)	ABCC6	Pathogenic	no assertion criteria provided
30339	NM_001171.6(ABCC6):c.1552C>T (p.Arg518Ter)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
30340	NM_001171.6(ABCC6):c.450dup (p.Ala151fs)	ABCC6	Pathogenic	no assertion criteria provided
3578536	NM_001171.6(ABCC6):c.4404-1G>A	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578626	NM_001171.6(ABCC6):c.341_345+8delinsG	ABCC6	Pathogenic	criteria provided, single submitter
372294	NM_001171.6(ABCC6):c.1132C>T (p.Gln378Ter)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
372295	NM_001171.6(ABCC6):c.3491G>A (p.Arg1164Gln)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
381638	NM_001171.6(ABCC6):c.2420G>A (p.Arg807Gln)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
418938	NM_001171.6(ABCC6):c.196dup (p.Ser66fs)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
430158	NM_001171.6(ABCC6):c.1256G>A (p.Arg419Gln)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433215	NM_001171.6(ABCC6):c.960del (p.Ser321fs)	ABCC6	Pathogenic	criteria provided, single submitter
433218	NM_001171.6(ABCC6):c.1087C>T (p.Gln363Ter)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
433232	NM_001171.6(ABCC6):c.1460G>A (p.Arg487Gln)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433243	NM_001171.6(ABCC6):c.1798C>T (p.Arg600Cys)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433256	NM_001171.6(ABCC6):c.1999del (p.Ala667fs)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433260	NM_001171.6(ABCC6):c.2162G>A (p.Trp721Ter)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
433266	NM_001171.6(ABCC6):c.2252T>A (p.Met751Lys)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433267	NM_001171.6(ABCC6):c.2263G>A (p.Gly755Arg)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433268	NM_001171.6(ABCC6):c.2278C>T (p.Arg760Trp)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433275	NM_001171.6(ABCC6):c.2432C>T (p.Thr811Met)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
433283	NM_001171.6(ABCC6):c.2542del (p.Met848fs)	ABCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433294	NM_001171.6(ABCC6):c.3823C>T (p.Arg1275Ter)	ABCC6	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
ABCC6	Definitive	Autosomal recessive	arterial calcification, generalized, of infancy, 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCC6	Orphanet:51608	Generalized arterial calcification of infancy
ABCC6	Orphanet:758	Pseudoxanthoma elasticum

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
ABCC6	HGNC:57	ENSG00000091262	O95255	ATP-binding cassette sub-family C member 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCC6	ATP-binding cassette sub-family C member 6	ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells.

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCC6	Transporter	yes	7.6.2.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, MRP

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
duodenum	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCC6	136		marker	right lobe of liver, liver, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCC6	186

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCC6	O95255	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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 ABCC6 causes PXE	1	11420.0×	5e-04	ABCC6
ABC transporter disorders	1	439.2×	0.007	ABCC6
Disorders of transmembrane transporters	1	139.3×	0.012	ABCC6
ABC-family protein mediated transport	1	121.5×	0.012	ABCC6
Transport of small molecules	1	25.1×	0.048	ABCC6
Disease	1	13.1×	0.076	ABCC6

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
inorganic diphosphate transport	1	8426.0×	0.001	ABCC6
inhibition of non-skeletal tissue mineralization	1	4213.0×	0.001	ABCC6
leukotriene transport	1	2407.4×	0.001	ABCC6
response to sodium phosphate	1	1685.2×	0.001	ABCC6
intracellular phosphate ion homeostasis	1	1532.0×	0.001	ABCC6
ATP transport	1	1404.3×	0.001	ABCC6
response to magnesium ion	1	1404.3×	0.001	ABCC6
phosphate ion homeostasis	1	1053.2×	0.002	ABCC6
ATP metabolic process	1	468.1×	0.003	ABCC6
calcium ion homeostasis	1	443.5×	0.003	ABCC6
transmembrane transport	1	168.5×	0.008	ABCC6
gene expression	1	79.9×	0.014	ABCC6
visual perception	1	79.5×	0.014	ABCC6
response to xenobiotic stimulus	1	69.1×	0.014	ABCC6

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
ABCC6	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
ABCC6	10	Functional:9, Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCC6	7.6.2.3	ABC-type glutathione-S-conjugate transporter

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	1	ABCC6
D	Druggable family + AlphaFold only, no drug	0
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)
ABCC6	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.