Amyotrophic lateral sclerosis type 21

disease

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Also known as ALS21amyotrophic lateral sclerosis 21amyotrophic lateral sclerosis caused by mutation in MATR3MATR3 amyotrophic lateral sclerosismyopathy, distal, 2vocal cord and pharyngeal dysfunction with distal myopathy

Summary

Amyotrophic lateral sclerosis type 21 (MONDO:0011632) is a disease caused by MATR3 (GenCC Strong), with 2 cohort genes.

At a glance

Causal gene: MATR3 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 575

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 21
Mondo ID	MONDO:0011632
OMIM	606070
DOID	DOID:0060212
NCIT	C168755
UMLS	C3807521
MedGen	813851
GARD	0018619
Is cancer (heuristic)	no

Also known as: ALS21 · amyotrophic lateral sclerosis 21 · amyotrophic lateral sclerosis caused by mutation in MATR3 · amyotrophic lateral sclerosis type 21 · MATR3 amyotrophic lateral sclerosis · myopathy, distal, 2 · vocal cord and pharyngeal dysfunction with distal myopathy

Data availability: 575 ClinVar variants · 4 GenCC gene-disease records · 12 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 21

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

575 retrieved; paginated sample, class counts are floors:

302 uncertain significance, 209 likely benign, 41 benign, 13 conflicting classifications of pathogenicity, 9 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14002	NM_018834.6(MATR3):c.254C>G (p.Ser85Cys)	MATR3	Pathogenic	criteria provided, multiple submitters, no conflicts
351133	NM_018834.6(MATR3):c.1991A>C (p.Glu664Ala)	LOC126807526	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1196920	NM_018834.6(MATR3):c.2251G>A (p.Ala751Thr)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2498982	NM_018834.6(MATR3):c.189A>G (p.Ser63=)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351128	NM_018834.6(MATR3):c.1734+11T>G	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351130	NM_018834.6(MATR3):c.1879C>G (p.Gln627Glu)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351134	NM_018834.6(MATR3):c.2031C>T (p.Asp677=)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351142	NM_018834.6(MATR3):c.2504A>G (p.Asn835Ser)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
651450	NM_018834.6(MATR3):c.1132G>A (p.Ala378Thr)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
771597	NM_018834.6(MATR3):c.1778+3A>G	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
772353	NM_018834.6(MATR3):c.2318A>C (p.Tyr773Ser)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
781861	NM_018834.6(MATR3):c.2114G>T (p.Ser705Ile)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906860	NM_018834.6(MATR3):c.675A>G (p.Arg225=)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906939	NM_018834.6(MATR3):c.2318A>G (p.Tyr773Cys)	MATR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060802	NM_018834.6(MATR3):c.2133G>C (p.Lys711Asn)	LOC126807526	Uncertain significance	criteria provided, single submitter
1163259	NM_018834.6(MATR3):c.2128G>A (p.Ala710Thr)	LOC126807526	Uncertain significance	criteria provided, multiple submitters, no conflicts
126562	NM_018834.6(MATR3):c.1864A>G (p.Thr622Ala)	LOC126807526	Uncertain significance	criteria provided, single submitter
1366676	NM_018834.6(MATR3):c.2120C>T (p.Ser707Leu)	LOC126807526	Uncertain significance	criteria provided, single submitter
1387469	NM_018834.6(MATR3):c.1880A>G (p.Gln627Arg)	LOC126807526	Uncertain significance	criteria provided, single submitter
1399904	NM_018834.6(MATR3):c.1929G>C (p.Gln643His)	LOC126807526	Uncertain significance	criteria provided, single submitter
1417532	NM_018834.6(MATR3):c.1915A>G (p.Thr639Ala)	LOC126807526	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426130	NM_018834.6(MATR3):c.1847A>G (p.Gln616Arg)	LOC126807526	Uncertain significance	criteria provided, single submitter
1447853	NM_018834.6(MATR3):c.1997C>T (p.Ala666Val)	LOC126807526	Uncertain significance	criteria provided, single submitter
1503590	NM_018834.6(MATR3):c.1913A>C (p.Asp638Ala)	LOC126807526	Uncertain significance	criteria provided, single submitter
1514491	NM_018834.6(MATR3):c.1949T>C (p.Met650Thr)	LOC126807526	Uncertain significance	criteria provided, single submitter
2047424	NM_018834.6(MATR3):c.1861T>G (p.Ser621Ala)	LOC126807526	Uncertain significance	criteria provided, multiple submitters, no conflicts
2047917	NM_018834.6(MATR3):c.1929G>T (p.Gln643His)	LOC126807526	Uncertain significance	criteria provided, single submitter
2098365	NM_018834.6(MATR3):c.1948A>G (p.Met650Val)	LOC126807526	Uncertain significance	criteria provided, single submitter
2147336	NM_018834.6(MATR3):c.2060T>G (p.Val687Gly)	LOC126807526	Uncertain significance	criteria provided, multiple submitters, no conflicts
2420321	NM_018834.6(MATR3):c.2107G>A (p.Asp703Asn)	LOC126807526	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
MATR3	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 21	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MATR3	Orphanet:600	Vocal cord and pharyngeal distal myopathy
MATR3	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MATR3	HGNC:6912	ENSG00000015479	P43243	Matrin-3	gencc,clinvar
SNHG4	HGNC:32964	ENSG00000281398		small nucleolar RNA host gene 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MATR3	Matrin-3	May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MATR3	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
SNHG4	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
cortical plate	1
ganglionic eminence	1
buccal mucosa cell	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MATR3	135	ubiquitous	marker	cortical plate, corpus callosum, ganglionic eminence
SNHG4	216	ubiquitous	marker	buccal mucosa cell, lower esophagus mucosa, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MATR3	3,804
SNHG4	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MATR3	P43243	57.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
heart valve development	1	1532.0×	0.002	MATR3
blastocyst formation	1	766.0×	0.002	MATR3
post-transcriptional regulation of gene expression	1	648.1×	0.002	MATR3
ventricular septum development	1	495.6×	0.002	MATR3
activation of innate immune response	1	481.5×	0.002	MATR3
innate immune response	1	33.6×	0.030	MATR3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MATR3	1	2
SNHG4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MATR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MATR3	7	Binding:7

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	MATR3

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	1	MATR3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SNHG4

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)
SNHG4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: MATR3, SNHG4