Amyotrophic lateral sclerosis type 9

Summary

Amyotrophic lateral sclerosis type 9 (MONDO:0012753) is a disease caused by ANG (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ANG (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 9
Mondo ID	MONDO:0012753
MeSH	C567499
OMIM	611895
DOID	DOID:0060200
UMLS	C2678468
MedGen	395629
GARD	0010498
Is cancer (heuristic)	no

Also known as: ALS9 · amyotrophic lateral sclerosis 9 · amyotrophic lateral sclerosis caused by mutation in ANG · amyotrophic lateral sclerosis type 9 · ANG amyotrophic lateral sclerosis

Data availability: 44 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

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 › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › amyotrophic lateral sclerosis type 9

Related subtypes (29): amyotrophic lateral sclerosis type 1, frontotemporal dementia and/or amyotrophic lateral sclerosis 1, spinocerebellar ataxia type 2, amyotrophic lateral sclerosis type 15, frontotemporal dementia and/or amyotrophic lateral sclerosis 7, amyotrophic lateral sclerosis type 4, amyotrophic lateral sclerosis type 21, amyotrophic lateral sclerosis type 3, amyotrophic lateral sclerosis type 6, amyotrophic lateral sclerosis type 7, amyotrophic lateral sclerosis type 8, amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis type 11, amyotrophic lateral sclerosis type 12, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, amyotrophic lateral sclerosis type 18, amyotrophic lateral sclerosis type 20, amyotrophic lateral sclerosis type 19, frontotemporal dementia and/or amyotrophic lateral sclerosis 2, amyotrophic lateral sclerosis type 22, frontotemporal dementia and/or amyotrophic lateral sclerosis 3, frontotemporal dementia and/or amyotrophic lateral sclerosis 4, juvenile amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 23, frontotemporal dementia and/or amyotrophic lateral sclerosis 8, frontotemporal dementia and/or amyotrophic lateral sclerosis 5, amyotrophic lateral sclerosis 26 with or without frontotemporal dementia, amyotrophic lateral sclerosis 27, juvenile, amyotrophic lateral sclerosis 28

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

44 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 10 benign, 6 pathogenic, 5 conflicting classifications of pathogenicity, 4 benign/likely benign, 4 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
18077	NM_001097577.3(ANG):c.189C>G (p.Cys63Trp)	ANG	Pathogenic	no assertion criteria provided
18082	NM_001097577.3(ANG):c.409G>A (p.Val137Ile)	ANG	Pathogenic	no assertion criteria provided
18073	NM_001097577.3(ANG):c.107A>T (p.Gln36Leu)	EGILA	Pathogenic	no assertion criteria provided
18075	NM_001097577.3(ANG):c.121A>G (p.Lys41Glu)	EGILA	Pathogenic	no assertion criteria provided
18078	NM_001097577.3(ANG):c.191A>T (p.Lys64Ile)	EGILA	Pathogenic	no assertion criteria provided
18076	NM_001097577.3(ANG):c.164G>A (p.Arg55Lys)	RNASE4	Pathogenic	no assertion criteria provided
18080	NM_001097577.3(ANG):c.155G>A (p.Ser52Asn)	ANG	Likely pathogenic	criteria provided, single submitter
18074	NM_001097577.3(ANG):c.122A>T (p.Lys41Ile)	ANG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18081	NM_001097577.3(ANG):c.407C>T (p.Pro136Leu)	ANG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807060	NM_001097577.3(ANG):c.3G>A (p.Met1Ile)	ANG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312776	NM_001097577.3(ANG):c.365C>T (p.Ala122Val)	EGILA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18079	NM_001097577.3(ANG):c.208A>G (p.Ile70Val)	RNASE4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312759	NM_001145.4(ANG):c.-594C>A	ANG	Uncertain significance	criteria provided, single submitter
312763	NM_001145.4(ANG):c.-524G>A	ANG	Uncertain significance	criteria provided, single submitter
312767	NM_001145.4(ANG):c.-381C>T	ANG	Uncertain significance	criteria provided, single submitter
312770	NM_001145.4(ANG):c.-115G>C	ANG	Uncertain significance	criteria provided, single submitter
881256	NM_001145.4(ANG):c.-542G>A	ANG	Uncertain significance	criteria provided, single submitter
881717	NM_001145.4(ANG):c.-168A>G	ANG	Uncertain significance	criteria provided, single submitter
882867	NM_001097577.3(ANG):c.62C>T (p.Pro21Leu)	ANG	Uncertain significance	criteria provided, multiple submitters, no conflicts
883658	NM_001097577.3(ANG):c.224G>A (p.Arg75His)	ANG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1366739	NM_001097577.3(ANG):c.433C>T (p.Arg145Cys)	EGILA	Uncertain significance	criteria provided, multiple submitters, no conflicts
881315	NM_001097577.3(ANG):c.*81A>C	EGILA	Uncertain significance	criteria provided, single submitter
882865	NM_001097577.3(ANG):c.38T>C (p.Val13Ala)	EGILA	Uncertain significance	criteria provided, multiple submitters, no conflicts
883659	NM_001097577.3(ANG):c.368G>A (p.Gly123Glu)	EGILA	Uncertain significance	criteria provided, single submitter
3779460	NM_001097577.3(ANG):c.146A>C (p.Tyr49Ser)	RNASE4	Uncertain significance	criteria provided, single submitter
882864	NM_001097577.3(ANG):c.-18-4G>A	RNASE4	Uncertain significance	criteria provided, single submitter
257559	NM_001097577.3(ANG):c.330T>G (p.Gly110=)	ANG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
312760	NM_001145.4(ANG):c.-579G>C	ANG	Benign	criteria provided, multiple submitters, no conflicts
312761	NM_001145.4(ANG):c.-534C>T	ANG	Benign	criteria provided, multiple submitters, no conflicts
312762	NM_001145.4(ANG):c.-530T>C	ANG	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
ANG	Definitive	Autosomal dominant	amyotrophic lateral sclerosis type 9	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANG	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANG	HGNC:483	ENSG00000214274	P03950	Angiogenin	gencc,clinvar
RNASE4	HGNC:10047	ENSG00000258818	P34096	Ribonuclease 4	clinvar
EGILA	HGNC:54482	ENSG00000258451		EGFR interacting lncRNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANG	Angiogenin	Secreted ribonuclease that can either promote or restrict cell proliferation of target cells, depending on the context.
RNASE4	Ribonuclease 4	Cleaves preferentially after uridine bases.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANG	Other/Unknown	no		RNaseA, RNaseA_AS, RNaseA_domain
RNASE4	Other/Unknown	no		RNaseA, RNaseA_AS, RNaseA_domain
EGILA	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	3
right lobe of liver	3
left ovary	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANG	238	ubiquitous	marker	right lobe of liver, liver, left ovary
RNASE4	134	ubiquitous	marker	right lobe of liver, liver, calcaneal tendon
EGILA	113	tissue_specific	marker	right lobe of liver, male germ line stem cell (sensu Vertebrata) in testis, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANG	852
RNASE4	275
EGILA	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANG	P03950	56
RNASE4	P34096	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis	1	3806.7×	0.002	ANG
Gene Silencing by RNA	1	356.9×	0.007	ANG
Adherens junctions interactions	1	248.3×	0.007	ANG
Cell-cell junction organization	1	248.3×	0.007	ANG
Cell junction organization	1	187.2×	0.007	ANG
Cell-Cell communication	1	137.6×	0.008	ANG
Gene expression (Transcription)	1	17.8×	0.056	ANG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
antibacterial humoral response	2	330.4×	2e-04	ANG, RNASE4
defense response to Gram-positive bacterium	2	127.7×	8e-04	ANG, RNASE4
negative regulation of translation in response to stress	1	2808.7×	0.003	ANG
tRNA decay	1	1685.2×	0.004	ANG
homeostatic process	1	842.6×	0.006	ANG
signaling	1	766.0×	0.006	ANG
rRNA transcription	1	495.6×	0.007	ANG
cell communication	1	421.3×	0.007	ANG
positive regulation of phosphorylation	1	421.3×	0.007	ANG
hematopoietic stem cell proliferation	1	324.1×	0.007	ANG
negative regulation of smooth muscle cell proliferation	1	312.1×	0.007	ANG
oocyte maturation	1	300.9×	0.007	ANG
stress granule assembly	1	300.9×	0.007	ANG
actin filament polymerization	1	240.7×	0.008	ANG
placenta development	1	221.7×	0.008	ANG
response to hormone	1	216.1×	0.008	ANG
ovarian follicle development	1	195.9×	0.008	ANG
positive regulation of protein secretion	1	172.0×	0.008	ANG
positive regulation of endothelial cell proliferation	1	115.4×	0.012	ANG
antimicrobial humoral immune response mediated by antimicrobial peptide	1	81.0×	0.016	ANG
response to hypoxia	1	47.9×	0.026	ANG
angiogenesis	1	31.2×	0.036	ANG
cell migration	1	30.8×	0.036	ANG
negative regulation of apoptotic process	1	17.4×	0.061	ANG
innate immune response	1	16.8×	0.061	ANG
signal transduction	1	8.0×	0.121	ANG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANG	0	0
RNASE4	0	0
EGILA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ANG	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	3	ANG, RNASE4, EGILA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANG	2	—
RNASE4	0	—
EGILA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.