Frontotemporal dementia and/or amyotrophic lateral sclerosis 3

Summary

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (MONDO:0014640) is a disease caused by SQSTM1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SQSTM1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Mondo ID	MONDO:0014640
OMIM	616437
DOID	DOID:0110068
UMLS	C4225326
MedGen	897127
GARD	0016113
Is cancer (heuristic)	no

Also known as: frontotemporal dementia and/or amyotrophic lateral sclerosis 3 · frontotemporal dementia and/or amyotrophic lateral sclerosis type 3 · FTDALS3

Data availability: 27 ClinVar variants · 2 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 › frontotemporal dementia and/or amyotrophic lateral sclerosis 3

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 9, 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 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

27 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 3 benign, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1458052	NM_003900.5(SQSTM1):c.1231G>A (p.Gly411Ser)	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976342	NM_003900.5(SQSTM1):c.1128del (p.Gly376_Leu377insTer)	SQSTM1	Likely pathogenic	criteria provided, single submitter
202211	NM_003900.5(SQSTM1):c.1160C>T (p.Pro387Leu)	SQSTM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
253029	NM_003900.5(SQSTM1):c.98C>T (p.Ala33Val)	SQSTM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8108	NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)	SQSTM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1412923	NM_002087.4(GRN):c.352AAC[1] (p.Asn119del)	GRN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2581000	NM_003900.5(SQSTM1):c.200A>G (p.Tyr67Cys)	LOC129995449	Uncertain significance	criteria provided, single submitter
1057481	NM_003900.5(SQSTM1):c.308A>G (p.Lys103Arg)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426786	NM_003900.5(SQSTM1):c.210G>C (p.Glu70Asp)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1678573	NM_003900.5(SQSTM1):c.1306C>T (p.His436Tyr)	SQSTM1	Uncertain significance	criteria provided, single submitter
1687257	NM_003900.5(SQSTM1):c.240C>G (p.Asp80Glu)	SQSTM1	Uncertain significance	criteria provided, single submitter
202213	NM_003900.5(SQSTM1):c.711GAA[1] (p.Lys238del)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2154966	NM_003900.5(SQSTM1):c.445G>A (p.Asp149Asn)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2577014	NM_003900.5(SQSTM1):c.1159C>G (p.Pro387Ala)	SQSTM1	Uncertain significance	criteria provided, single submitter
3780664	NM_003900.5(SQSTM1):c.98C>A (p.Ala33Glu)	SQSTM1	Uncertain significance	criteria provided, single submitter
3892555	NM_003900.5(SQSTM1):c.223G>A (p.Val75Ile)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
571746	NM_003900.5(SQSTM1):c.457G>A (p.Val153Ile)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
844068	NM_003900.5(SQSTM1):c.1277C>T (p.Ala426Val)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
857901	NM_003900.5(SQSTM1):c.625C>T (p.Arg209Cys)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
906314	NM_003900.5(SQSTM1):c.50C>T (p.Ala17Val)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
947710	NM_003900.5(SQSTM1):c.1313C>T (p.Pro438Leu)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
975908	NM_003900.5(SQSTM1):c.-27C>T	SQSTM1	Uncertain significance	criteria provided, single submitter
1248589	NM_003900.5(SQSTM1):c.755-23G>A	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
259189	NM_003900.5(SQSTM1):c.876C>T (p.Asp292=)	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
259191	NM_003900.5(SQSTM1):c.936G>A (p.Arg312=)	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
475410	NM_003900.5(SQSTM1):c.984G>A (p.Ser328=)	SQSTM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
542164	NM_003900.5(SQSTM1):c.1176G>A (p.Pro392=)	SQSTM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 8 · 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
SQSTM1	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 3	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis
GRN	Orphanet:100069	Semantic dementia
GRN	Orphanet:100070	Progressive non-fluent aphasia
GRN	Orphanet:275864	Behavioral variant of frontotemporal dementia
GRN	Orphanet:314629	CLN11 disease

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
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	gencc,clinvar
GRN	HGNC:4601	ENSG00000030582	P28799	Progranulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.
GRN	Progranulin	Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation.

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)
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf
GRN	Other/Unknown	no		Granulin, Granulin_sf, Granulin_fam

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
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
granulocyte	1
monocyte	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
GRN	301	ubiquitous	marker	monocyte, granulocyte, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SQSTM1	7,269
GRN	1,490

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SQSTM1	Q13501	26
GRN	P28799	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
p75NTR signals via NF-kB	1	951.7×	0.015	SQSTM1
Mitophagy	1	519.1×	0.015	SQSTM1
Pexophagy	1	475.8×	0.015	SQSTM1
p75NTR recruits signalling complexes	1	439.2×	0.015	SQSTM1
NF-kB is activated and signals survival	1	439.2×	0.015	SQSTM1
NRIF signals cell death from the nucleus	1	356.9×	0.015	SQSTM1
PINK1-PRKN Mediated Mitophagy	1	178.4×	0.021	SQSTM1
Nuclear events mediated by NFE2L2	1	167.9×	0.021	SQSTM1
Selective autophagy	1	139.3×	0.021	SQSTM1
Interleukin-1 family signaling	1	135.9×	0.021	SQSTM1
Signaling by ALK in cancer	1	135.9×	0.021	SQSTM1
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.024	SQSTM1
p75 NTR receptor-mediated signalling	1	93.6×	0.026	SQSTM1
Signaling by ALK fusions and activated point mutants	1	75.1×	0.027	SQSTM1
Autophagy	1	74.2×	0.027	SQSTM1
Cellular response to chemical stress	1	71.4×	0.027	SQSTM1
Death Receptor Signaling	1	69.6×	0.027	SQSTM1
Interleukin-1 signaling	1	62.1×	0.028	SQSTM1
KEAP1-NFE2L2 pathway	1	60.1×	0.028	SQSTM1
Macroautophagy	1	57.7×	0.028	SQSTM1
Signaling by Interleukins	1	32.1×	0.047	SQSTM1
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.051	SQSTM1
Neddylation	1	23.7×	0.058	SQSTM1
Cytokine Signaling in Immune system	1	20.4×	0.065	SQSTM1
Cellular responses to stress	1	18.4×	0.069	SQSTM1
Cellular responses to stimuli	1	15.7×	0.077	SQSTM1
Neutrophil degranulation	1	11.5×	0.101	GRN
Post-translational protein modification	1	9.6×	0.116	SQSTM1
Disease	1	6.5×	0.158	SQSTM1
Immune System	1	6.5×	0.158	SQSTM1

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
positive regulation of aspartic-type peptidase activity	1	8426.0×	0.004	GRN
positive regulation of inflammatory response to wounding	1	4213.0×	0.004	GRN
positive regulation of trophectodermal cell proliferation	1	4213.0×	0.004	GRN
brown fat cell proliferation	1	2808.7×	0.004	SQSTM1
protein targeting to vacuole involved in autophagy	1	2808.7×	0.004	SQSTM1
positive regulation of protein folding	1	2808.7×	0.004	GRN
astrocyte activation involved in immune response	1	2106.5×	0.004	GRN
positive regulation of lysosome organization	1	2106.5×	0.004	GRN
trophectodermal cell proliferation	1	1685.2×	0.004	GRN
microglial cell activation involved in immune response	1	1685.2×	0.004	GRN
positive regulation of axon regeneration	1	1685.2×	0.004	GRN
negative regulation of respiratory burst involved in inflammatory response	1	1685.2×	0.004	GRN
response to mitochondrial depolarisation	1	1404.3×	0.004	SQSTM1
negative regulation of neutrophil activation	1	1203.7×	0.004	GRN
negative regulation of microglial cell activation	1	1053.2×	0.004	GRN
regulation of Ras protein signal transduction	1	936.2×	0.004	SQSTM1
positive regulation of defense response to bacterium	1	936.2×	0.004	GRN
aggrephagy	1	842.6×	0.005	SQSTM1
maintenance of synapse structure	1	766.0×	0.005	GRN
protein localization to perinuclear region of cytoplasm	1	702.2×	0.005	SQSTM1
negative regulation of toll-like receptor 4 signaling pathway	1	561.7×	0.005	SQSTM1
membraneless organelle assembly	1	561.7×	0.005	SQSTM1
pexophagy	1	526.6×	0.005	SQSTM1
regulation of protein complex stability	1	526.6×	0.005	SQSTM1
lysosomal protein catabolic process	1	526.6×	0.005	GRN
locomotory exploration behavior	1	495.6×	0.006	GRN
regulation of mitochondrion organization	1	421.3×	0.006	SQSTM1
cellular response to stress	1	421.3×	0.006	SQSTM1
negative regulation of ferroptosis	1	401.2×	0.006	SQSTM1
autophagy of mitochondrion	1	366.4×	0.006	SQSTM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SQSTM1	0	0
GRN	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
SQSTM1	20	Binding:20
GRN	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	2	SQSTM1, GRN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SQSTM1	20	—
GRN	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.