Autosomal recessive distal spinal muscular atrophy 1

Summary

Autosomal recessive distal spinal muscular atrophy 1 (MONDO:0011436) is a disease caused by IGHMBP2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IGHMBP2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,224
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		128	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive distal spinal muscular atrophy 1
Mondo ID	MONDO:0011436
MeSH	C536880
OMIM	604320
Orphanet	98920
DOID	DOID:0111064
SNOMED CT	711483003
UMLS	C1858517
MedGen	388083
GARD	0008592
NORD	1994
Is cancer (heuristic)	no

Also known as: autosomal recessive distal spinal muscular atrophy 1 · autosomal recessive distal spinal muscular atrophy type 1 · autosomal recessive spinal muscular atrophy with respiratory distress · dHMN6 · diaphragmatic spinal muscular atrophy · distal hereditary motor neuropathy type 6 · distal-HMN type 6 · DSMA1 · dSMA1 · HMN VI · IGHMBP2 spinal muscular atrophy · neuronopathy, distal hereditary motor, type VI · severe infantile axonal neuropathy with respiratory failure type 1 · SIANRF · SMARD1 · spinal muscular atrophy caused by mutation in IGHMBP2 · Spinal Muscular Atrophy with Respiratory Distress · spinal muscular atrophy with respiratory distress type 1 · spinal muscular atrophy, distal, autosomal recessive, 1 · spinal muscular atrophy, distal, autosomal recessive, type 1

Data availability: 1,224 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › autosomal recessive distal spinal muscular atrophy 1

Related subtypes (18): spinal muscular atrophy-progressive myoclonic epilepsy syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, facioscapulohumeral type, adult-onset proximal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, segmental, spinal muscular atrophy, Ryukyuan type, scapuloperoneal spinal muscular atrophy, autosomal recessive, X-linked distal spinal muscular atrophy type 3, infantile-onset X-linked spinal muscular atrophy, autosomal recessive distal spinal muscular atrophy 2, neuronopathy, distal hereditary motor, autosomal recessive 3, neuronopathy, distal hereditary motor, autosomal recessive 4, neuronopathy, distal hereditary motor, autosomal recessive 5, neuronopathy, distal hereditary motor, autosomal dominant, bulbospinal muscular atrophy, spinal muscular atrophy with respiratory distress type 2, proximal spinal muscular atrophy, spinal muscular atrophy type 0

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

600 retrieved; paginated sample, class counts are floors:

305 likely benign, 170 uncertain significance, 33 conflicting classifications of pathogenicity, 32 pathogenic, 18 benign, 16 pathogenic/likely pathogenic, 16 benign/likely benign, 10 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066593	NM_002180.3(IGHMBP2):c.1730T>G (p.Leu577Arg)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070991	NM_002180.3(IGHMBP2):c.763_767del (p.Leu255fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1073962	NC_000011.9:g.(?68671411)(68707209_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter
1075876	NM_002180.3(IGHMBP2):c.373C>T (p.Gln125Ter)	IGHMBP2	Pathogenic	criteria provided, single submitter
1175183	NM_002180.3(IGHMBP2):c.1061-2A>G	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1299363	NM_002180.3(IGHMBP2):c.2796del (p.Cys932fs)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1371633	NM_002180.3(IGHMBP2):c.696_700del (p.Lys233fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1379465	NM_002180.3(IGHMBP2):c.1305_1350del (p.Arg436fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1393140	NM_002180.3(IGHMBP2):c.467del (p.Lys156fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1426154	NM_002180.3(IGHMBP2):c.1477A>G (p.Thr493Ala)	IGHMBP2	Pathogenic	criteria provided, single submitter
1451211	NM_002180.3(IGHMBP2):c.211C>T (p.Arg71Ter)	IGHMBP2	Pathogenic	criteria provided, single submitter
1468031	NM_002180.3(IGHMBP2):c.1126G>A (p.Glu376Lys)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162194	NM_002180.3(IGHMBP2):c.138T>A (p.Cys46Ter)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
162195	NM_002180.3(IGHMBP2):c.2911_2912del (p.Arg971fs)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1945190	NM_002180.3(IGHMBP2):c.891del (p.Lys298fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
2033010	NM_002180.3(IGHMBP2):c.317_318insA (p.Thr107fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
204303	NM_002180.3(IGHMBP2):c.449+1G>T	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204304	NM_002180.3(IGHMBP2):c.2784+1G>T	IGHMBP2	Pathogenic	criteria provided, single submitter
2130513	NM_002180.3(IGHMBP2):c.1919_1920dup (p.Glu641fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
2157555	NM_002180.3(IGHMBP2):c.1969dup (p.Gln657fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
217448	NM_002180.3(IGHMBP2):c.2T>C (p.Met1Thr)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217449	NM_002180.3(IGHMBP2):c.983_987del (p.Lys328fs)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217450	NM_002180.3(IGHMBP2):c.1478C>T (p.Thr493Ile)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228355	NM_002180.3(IGHMBP2):c.127C>T (p.Arg43Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234316	NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235774	NM_002180.3(IGHMBP2):c.1808G>A (p.Arg603His)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2424363	NC_000011.9:g.(?68671421)(68679091_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter
2424364	NC_000011.9:g.(?68673517)(68682511_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter
2424365	NC_000011.9:g.(?68682271)(68682511_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter
242498	NM_002180.3(IGHMBP2):c.660A>C (p.Lys220Asn)	IGHMBP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
IGHMBP2	Definitive	Autosomal recessive	autosomal recessive distal spinal muscular atrophy 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress 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
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase

Expression context

Cohort genes with no expression data: 0.

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
esophagogastric junction muscularis propria	1
lower esophagus muscularis layer	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IGHMBP2	1,265

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IGHMBP2	P38935	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
IGHMBP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IGHMBP2	3.6.4.12	DNA helicase

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	IGHMBP2

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)
IGHMBP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05152823	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Gene Therapy for IGHMBP2-Related Diseases