Spinal muscular atrophy with congenital bone fractures 2

Summary

Spinal muscular atrophy with congenital bone fractures 2 (MONDO:0014807) is a disease caused by ASCC1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ASCC1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spinal muscular atrophy with congenital bone fractures 2
Mondo ID	MONDO:0014807
OMIM	616867
UMLS	C4225176
MedGen	907910
GARD	0018495
Is cancer (heuristic)	no

Also known as: ASCC1 prenatal-onset spinal muscular atrophy with congenital bone fractures · prenatal-onset spinal muscular atrophy with congenital bone fractures caused by mutation in ASCC1 · SMABF2 · spinal muscular atrophy with congenital bone fractures 2 · spinal muscular atrophy with congenital bone fractures type 2

Data availability: 24 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › prenatal-onset spinal muscular atrophy with congenital bone fractures › spinal muscular atrophy with congenital bone fractures 2

Related subtypes (1): spinal muscular atrophy with congenital bone fractures 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

24 retrieved; paginated sample, class counts are floors:

11 pathogenic, 4 pathogenic/likely pathogenic, 4 likely pathogenic, 3 uncertain significance, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029240	NM_001198800.3(ASCC1):c.784C>T (p.Gln262Ter)	ASCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1210120	NC_000010.10:g.(?73970434)(73973122_?)del	ASCC1	Pathogenic	criteria provided, single submitter
1252053	NM_001198800.3(ASCC1):c.871+1G>A	ASCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301895	NM_001198800.3(ASCC1):c.349C>T (p.Arg117Ter)	ASCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1333815	NM_001198800.3(ASCC1):c.583C>T (p.Gln195Ter)	ASCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224639	NM_001198800.3(ASCC1):c.157dup (p.Glu53fs)	ASCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500145	NC_000010.11:g.72138925_72163147del	ASCC1	Pathogenic	no assertion criteria provided
2506360	NM_001198800.3(ASCC1):c.464_465del (p.Glu155fs)	ASCC1	Pathogenic	criteria provided, single submitter
3340123	NM_001198800.3(ASCC1):c.79C>T (p.Gln27Ter)	ASCC1	Pathogenic	criteria provided, single submitter
619021	NM_001198800.3(ASCC1):c.626+1G>A	ASCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801334	NM_001198800.3(ASCC1):c.382C>T (p.Arg128Ter)	ASCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
801335	NM_001198800.3(ASCC1):c.328C>T (p.Arg110Ter)	ASCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
801336	NG_031890.1:g.(?60461)(94053_?)del	ASCC1	Pathogenic	no assertion criteria provided
801337	NM_001198800.3(ASCC1):c.943C>T (p.Arg315Ter)	ASCC1	Pathogenic	no assertion criteria provided
985781	NM_001198800.3(ASCC1):c.311-2A>G	ASCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
3062021	NM_001198800.3(ASCC1):c.213-8T>G	ASCC1	Likely pathogenic	criteria provided, single submitter
3377184	NM_001198800.3(ASCC1):c.626+2T>A	ASCC1	Likely pathogenic	criteria provided, single submitter
3377590	NM_001198800.3(ASCC1):c.380_381del (p.Phe127fs)	ASCC1	Likely pathogenic	criteria provided, single submitter
4294356	NM_001198800.3(ASCC1):c.473T>C (p.Leu158Pro)	ASCC1	Likely pathogenic	criteria provided, single submitter
714485	NM_001198800.3(ASCC1):c.107A>G (p.Tyr36Cys)	ASCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1327920	NM_001198800.3(ASCC1):c.813G>A (p.Trp271Ter)	ASCC1	Uncertain significance	criteria provided, single submitter
1493896	NM_001198800.3(ASCC1):c.747-10A>G	ASCC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3130217	NM_001198800.3(ASCC1):c.829C>T (p.His277Tyr)	ASCC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
31129	NM_001198800.3(ASCC1):c.869A>G (p.Asn290Ser)	ASCC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ASCC1	Definitive	Autosomal recessive	spinal muscular atrophy with congenital bone fractures 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASCC1	Orphanet:486811	Prenatal-onset spinal muscular atrophy with congenital bone fractures

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
ASCC1	HGNC:24268	ENSG00000138303	Q8N9N2	Activating signal cointegrator 1 complex subunit 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASCC1	Activating signal cointegrator 1 complex subunit 1	Plays a role in DNA damage repair as component of the ASCC complex.

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)
ASCC1	Other/Unknown	no		KH_dom_type_1, Cyclic_Pdiesterase, ASCC1

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
calcaneal tendon	1
sperm	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASCC1	282	ubiquitous	marker	calcaneal tendon, ventricular zone, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASCC1	1,500

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASCC1	Q8N9N2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
ALKBH3 mediated reversal of alkylation damage	1	2855.0×	8e-04	ASCC1
DNA Damage Reversal	1	1631.4×	8e-04	ASCC1
Reversal of alkylation damage by DNA dioxygenases	1	1631.4×	8e-04	ASCC1
DNA Repair	1	98.5×	0.010	ASCC1

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
DNA alkylation repair	1	1532.0×	0.002	ASCC1
DNA replication	1	165.2×	0.009	ASCC1
regulation of DNA-templated transcription	1	31.6×	0.032	ASCC1

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
ASCC1	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	ASCC1

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)
ASCC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.