Amyotrophic lateral sclerosis type 12

disease

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Also known as ALS12amyotrophic lateral sclerosis 12amyotrophic lateral sclerosis 12 with or without frontotemporal dementiaamyotrophic lateral sclerosis caused by mutation in OPTNOPTN amyotrophic lateral sclerosis

Summary

Amyotrophic lateral sclerosis type 12 (MONDO:0013264) is a disease caused by OPTN (GenCC Definitive), with 2 cohort genes.

At a glance

Causal gene: OPTN (GenCC Definitive)
Cohort genes: 2
ClinVar variants: 426

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 12
Mondo ID	MONDO:0013264
OMIM	613435
DOID	DOID:0060203
UMLS	C3150692
MedGen	462042
GARD	0015663
Is cancer (heuristic)	no

Also known as: ALS12 · amyotrophic lateral sclerosis 12 · amyotrophic lateral sclerosis 12 with or without frontotemporal dementia · amyotrophic lateral sclerosis caused by mutation in OPTN · amyotrophic lateral sclerosis type 12 · OPTN amyotrophic lateral sclerosis

Data availability: 426 ClinVar variants · 6 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 › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › amyotrophic lateral sclerosis type 12

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

426 retrieved; paginated sample, class counts are floors:

209 uncertain significance, 100 likely benign, 38 pathogenic, 21 conflicting classifications of pathogenicity, 20 benign, 16 likely pathogenic, 11 pathogenic/likely pathogenic, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
584050	NC_000010.10:g.(?12833157)(13178866_?)del	CAMK1D	Pathogenic	criteria provided, single submitter
1323386	NM_001008212.2(OPTN):c.76dup (p.His26fs)	LOC108903148	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2929988	NM_001008212.2(OPTN):c.241G>T (p.Glu81Ter)	LOC108903148	Pathogenic	criteria provided, single submitter
3776024	NM_001008212.2(OPTN):c.331_334dup (p.Gly112fs)	LOC108903148	Pathogenic	criteria provided, single submitter
4792704	NM_001008212.2(OPTN):c.148del (p.Glu50fs)	LOC108903148	Pathogenic	criteria provided, single submitter
489125	NM_001008212.2(OPTN):c.127C>T (p.Gln43Ter)	LOC108903148	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7100	NM_001008212.2(OPTN):c.166+349_370-945del	LOC108903148	Pathogenic	no assertion criteria provided
529764	NC_000010.11:g.(?13109103)(13136886_?)del	LOC108903149	Pathogenic	criteria provided, single submitter
1384838	NC_000010.11:g.13122383AG[1]	OPTN	Pathogenic	criteria provided, single submitter
1409027	NM_001008212.2(OPTN):c.1241_1242del (p.Glu414fs)	OPTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425874	NC_000010.10:g.(?13151123)(13178866_?)del	OPTN	Pathogenic	criteria provided, single submitter
1451918	NM_001008212.2(OPTN):c.986_990del (p.Arg329fs)	OPTN	Pathogenic	criteria provided, single submitter
1455344	NM_001008212.2(OPTN):c.785C>A (p.Ser262Ter)	OPTN	Pathogenic	criteria provided, multiple submitters, no conflicts
1459219	NC_000010.10:g.(?13158247)(13158360_?)del	OPTN	Pathogenic	criteria provided, single submitter
1459834	NC_000010.10:g.(?13152254)(13161060_?)del	OPTN	Pathogenic	criteria provided, single submitter
1775090	NM_001008212.2(OPTN):c.1003C>T (p.Gln335Ter)	OPTN	Pathogenic	criteria provided, multiple submitters, no conflicts
1801690	NM_001008212.2(OPTN):c.493C>T (p.Gln165Ter)	OPTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191266	NM_001008212.2(OPTN):c.918_922del (p.Thr307fs)	OPTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1917899	NM_001008212.2(OPTN):c.1195G>T (p.Glu399Ter)	OPTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2042501	NM_001008212.2(OPTN):c.1289_1290del (p.Leu430fs)	OPTN	Pathogenic	criteria provided, single submitter
2061646	NM_001008212.2(OPTN):c.235C>T (p.Gln79Ter)	OPTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2090693	NM_001008212.2(OPTN):c.666del (p.Lys223fs)	OPTN	Pathogenic	criteria provided, single submitter
2126803	NM_001008212.2(OPTN):c.649A>T (p.Arg217Ter)	OPTN	Pathogenic	criteria provided, single submitter
2198963	NM_001008212.2(OPTN):c.1552C>T (p.Gln518Ter)	OPTN	Pathogenic	criteria provided, single submitter
2426699	NC_000010.10:g.(?13151123)(13158360_?)del	OPTN	Pathogenic	criteria provided, single submitter
2426700	NC_000010.10:g.(?13154433)(13161060_?)del	OPTN	Pathogenic	criteria provided, single submitter
2426701	NC_000010.10:g.(?13164365)(13168059_?)del	OPTN	Pathogenic	criteria provided, single submitter
2636905	NM_001008212.2(OPTN):c.1204_1210del (p.Asn401_Asn402insTer)	OPTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2928942	NM_001008212.2(OPTN):c.1318_1334dup (p.Asp445fs)	OPTN	Pathogenic	criteria provided, single submitter
2931123	NM_001008212.2(OPTN):c.523del (p.Glu175fs)	OPTN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
OPTN	Definitive	Semidominant	amyotrophic lateral sclerosis type 12	9

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OPTN	HGNC:17142	ENSG00000123240	Q96CV9	Optineurin	gencc,clinvar
CAMK1D	HGNC:19341	ENSG00000183049	Q8IU85	Calcium/calmodulin-dependent protein kinase type 1D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OPTN	Optineurin	Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8.
CAMK1D	Calcium/calmodulin-dependent protein kinase type 1D	Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and res…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OPTN	Other/Unknown	no		NEMO_N, CC2-LZ_dom, NEMO_ZF
CAMK1D	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
amniotic fluid	1
gastrocnemius	1
muscle of leg	1
middle temporal gyrus	1
parietal lobe	1
postcentral gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OPTN	302	ubiquitous	marker	amniotic fluid, gastrocnemius, muscle of leg
CAMK1D	260	ubiquitous	marker	middle temporal gyrus, parietal lobe, postcentral gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OPTN	3,505
CAMK1D	2,071

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OPTN	Q96CV9	14
CAMK1D	Q8IU85	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 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
Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation	1	951.7×	0.004	OPTN
TICAM1-dependent activation of IRF3/IRF7	1	815.7×	0.004	OPTN
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	1	761.3×	0.004	OPTN
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	601.0×	0.004	OPTN
TNFR1-induced proapoptotic signaling	1	439.2×	0.004	OPTN
PINK1-PRKN Mediated Mitophagy	1	356.9×	0.004	OPTN
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.004	OPTN
TBC/RABGAPs	1	259.6×	0.005	OPTN
Regulation of TNFR1 signaling	1	223.9×	0.005	OPTN
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.008	OPTN

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
regulation of granulocyte chemotaxis	1	8426.0×	0.003	CAMK1D
negative regulation of receptor recycling	1	1685.2×	0.004	OPTN
positive regulation of respiratory burst	1	1685.2×	0.004	CAMK1D
type 2 mitophagy	1	1685.2×	0.004	OPTN
cell death	1	1053.2×	0.004	OPTN
positive regulation of xenophagy	1	1053.2×	0.004	OPTN
obsolete positive regulation of CREB transcription factor activity	1	842.6×	0.004	CAMK1D
Golgi ribbon formation	1	766.0×	0.004	OPTN
cellular response to unfolded protein	1	495.6×	0.005	OPTN
regulation of dendrite development	1	495.6×	0.005	CAMK1D
protein localization to Golgi apparatus	1	401.2×	0.006	OPTN
positive regulation of neutrophil chemotaxis	1	324.1×	0.007	CAMK1D
Golgi to plasma membrane protein transport	1	263.3×	0.007	OPTN
regulation of canonical NF-kappaB signal transduction	1	240.7×	0.007	OPTN
signal transduction	2	16.1×	0.007	OPTN, CAMK1D
regulation of neuron projection development	1	216.1×	0.008	CAMK1D
positive regulation of phagocytosis	1	159.0×	0.010	CAMK1D
positive regulation of autophagy	1	104.0×	0.014	OPTN
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.016	OPTN
defense response to Gram-negative bacterium	1	84.3×	0.016	OPTN
positive regulation of neuron projection development	1	68.5×	0.018	CAMK1D
Golgi organization	1	66.9×	0.018	OPTN
positive regulation of apoptotic process	1	28.4×	0.041	CAMK1D
nervous system development	1	23.0×	0.048	CAMK1D
inflammatory response	1	18.9×	0.057	CAMK1D
negative regulation of apoptotic process	1	17.4×	0.059	CAMK1D
innate immune response	1	16.8×	0.059	OPTN

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CAMK1D	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CAMK1D	25	4
OPTN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CAMK1D
RUXOLITINIB	4	CAMK1D
NERATINIB	4	CAMK1D
ENTRECTINIB	4	CAMK1D
TOFACITINIB CITRATE	4	CAMK1D
TOFACITINIB	4	CAMK1D
BOSUTINIB	4	CAMK1D
UPADACITINIB	4	CAMK1D
NINTEDANIB	4	CAMK1D
SUNITINIB	4	CAMK1D
MIDOSTAURIN	4	CAMK1D
LESTAURTINIB	3	CAMK1D
RUBOXISTAURIN	3	CAMK1D
FORETINIB	2	CAMK1D
SU-014813	2	CAMK1D
ILORASERTIB	2	CAMK1D
R-406	2	CAMK1D
BI-2536	2	CAMK1D
SOTRASTAURIN	2	CAMK1D
TOZASERTIB	2	CAMK1D
PELITINIB	2	CAMK1D
KW-2449	1	CAMK1D
RG-1530	1	CAMK1D
GSK-690693	1	CAMK1D
AST-487	1	CAMK1D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CAMK1D	276	Binding:274, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAMK1D	2.7.11.17	Ca2+/calmodulin-dependent protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CAMK1D	276

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

25 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)
FEDRATINIB	4	CAMK1D
RUXOLITINIB	4	CAMK1D
NERATINIB	4	CAMK1D
ENTRECTINIB	4	CAMK1D
TOFACITINIB CITRATE	4	CAMK1D
TOFACITINIB	4	CAMK1D
BOSUTINIB	4	CAMK1D
UPADACITINIB	4	CAMK1D
NINTEDANIB	4	CAMK1D
SUNITINIB	4	CAMK1D
MIDOSTAURIN	4	CAMK1D
LESTAURTINIB	3	CAMK1D
RUBOXISTAURIN	3	CAMK1D
FORETINIB	2	CAMK1D
SU-014813	2	CAMK1D
ILORASERTIB	2	CAMK1D
R-406	2	CAMK1D
BI-2536	2	CAMK1D
SOTRASTAURIN	2	CAMK1D
TOZASERTIB	2	CAMK1D
PELITINIB	2	CAMK1D
KW-2449	1	CAMK1D
RG-1530	1	CAMK1D
GSK-690693	1	CAMK1D
AST-487	1	CAMK1D

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CAMK1D
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	OPTN

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)
OPTN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: OPTN, CAMK1D