Frontotemporal dementia and/or amyotrophic lateral sclerosis 2

Summary

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (MONDO:0014395) is a disease caused by CHCHD10 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: CHCHD10 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 224

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	frontotemporal dementia and/or amyotrophic lateral sclerosis 2
Mondo ID	MONDO:0014395
OMIM	615911
DOID	DOID:0060214
UMLS	C4014648
MedGen	863085
GARD	0018397
Is cancer (heuristic)	no

Also known as: frontotemporal dementia and/or amyotrophic lateral sclerosis 2 · frontotemporal dementia and/or amyotrophic lateral sclerosis type 2 · FTDALS2

Data availability: 224 ClinVar variants · 2 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 › frontotemporal dementia and/or amyotrophic lateral sclerosis 2

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, 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

224 retrieved; paginated sample, class counts are floors:

117 uncertain significance, 78 likely benign, 12 conflicting classifications of pathogenicity, 8 benign/likely benign, 6 benign, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
140745	NM_213720.3(CHCHD10):c.176C>T (p.Ser59Leu)	CHCHD10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452852	NM_213720.3(CHCHD10):c.44_45delinsTT (p.Arg15Leu)	CHCHD10	Pathogenic	criteria provided, single submitter
180220	NM_213720.3(CHCHD10):c.44G>T (p.Arg15Leu)	CHCHD10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1080264	NM_213720.3(CHCHD10):c.42-5C>T	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446575	NM_213720.3(CHCHD10):c.42-5C>G	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204292	NM_213720.3(CHCHD10):c.239C>T (p.Pro80Leu)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2061695	NM_213720.3(CHCHD10):c.261+10_261+11delinsAG	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2922669	NM_213720.3(CHCHD10):c.215C>T (p.Ala72Val)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473421	NM_213720.3(CHCHD10):c.214G>A (p.Ala72Thr)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
540611	NM_213720.3(CHCHD10):c.274G>A (p.Ala92Thr)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
565755	NM_213720.3(CHCHD10):c.312C>G (p.Tyr104Ter)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
567906	NM_213720.3(CHCHD10):c.276T>A (p.Ala92=)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
640736	NM_213720.3(CHCHD10):c.224G>A (p.Gly75Glu)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
655998	NM_213720.3(CHCHD10):c.196G>A (p.Gly66Ser)	CHCHD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
42016	NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)	SPG7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
665651	NC_000022.10:g.(?24108011)(24110169_?)dup	C22orf15	Uncertain significance	criteria provided, single submitter
831034	NC_000022.11:g.(?23765824)(23767603_?)del	C22orf15	Uncertain significance	criteria provided, single submitter
1000426	NM_213720.3(CHCHD10):c.2T>G (p.Met1Arg)	CHCHD10	Uncertain significance	criteria provided, single submitter
1003466	NM_213720.3(CHCHD10):c.8G>C (p.Arg3Pro)	CHCHD10	Uncertain significance	criteria provided, single submitter
1021740	NM_213720.3(CHCHD10):c.235G>A (p.Glu79Lys)	CHCHD10	Uncertain significance	criteria provided, single submitter
1026524	NM_213720.3(CHCHD10):c.409+1G>A	CHCHD10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1036655	NM_213720.3(CHCHD10):c.263C>A (p.Ala88Asp)	CHCHD10	Uncertain significance	criteria provided, single submitter
1040911	NM_213720.3(CHCHD10):c.55C>T (p.Pro19Ser)	CHCHD10	Uncertain significance	criteria provided, single submitter
1043025	NC_000022.10:g.(?24109541)(24110081_?)del	CHCHD10	Uncertain significance	criteria provided, single submitter
1043375	NM_213720.3(CHCHD10):c.42-2A>G	CHCHD10	Uncertain significance	criteria provided, single submitter
1052112	NM_213720.3(CHCHD10):c.302C>T (p.Pro101Leu)	CHCHD10	Uncertain significance	criteria provided, single submitter
1313416	NM_213720.3(CHCHD10):c.211G>A (p.Gly71Arg)	CHCHD10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1339018	NM_213720.3(CHCHD10):c.82C>T (p.Pro28Ser)	CHCHD10	Uncertain significance	criteria provided, single submitter
1352828	NM_213720.3(CHCHD10):c.350G>A (p.Ser117Asn)	CHCHD10	Uncertain significance	criteria provided, single submitter
1387504	NM_213720.3(CHCHD10):c.308C>T (p.Ala103Val)	CHCHD10	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
CHCHD10	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHCHD10	Orphanet:275872	Frontotemporal dementia with motor neuron disease
CHCHD10	Orphanet:276435	Lower motor neuron syndrome with late-adult onset
CHCHD10	Orphanet:457050	Autosomal dominant mitochondrial myopathy with exercise intolerance
CHCHD10	Orphanet:803	Amyotrophic lateral sclerosis
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHCHD10	HGNC:15559	ENSG00000250479	Q8WYQ3	Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial	gencc,clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
C22orf15	HGNC:15558	ENSG00000169314	Q8WYQ4	Uncharacterized protein C22orf15	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHCHD10	Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial	May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHCHD10	Other/Unknown	no		CHCH, CHCHD2/10-like
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
C22orf15	Other/Unknown	no		CXorf65-like

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
apex of heart	1
heart left ventricle	1
hindlimb stylopod muscle	1
left lobe of thyroid gland	1
primordial germ cell in gonad	1
sural nerve	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHCHD10	133	ubiquitous	marker	apex of heart, heart left ventricle, hindlimb stylopod muscle
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
C22orf15	123		marker	right uterine tube, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPG7	3,970
CHCHD10	1,344
C22orf15	152

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHCHD10	Q8WYQ3	5
SPG7	Q9UQ90	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C22orf15	Q8WYQ4	76.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 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
Processing of SMDT1	1	317.2×	0.011	SPG7
Mitochondrial calcium ion transport	1	271.9×	0.011	SPG7
Mitochondrial protein import	1	84.0×	0.024	CHCHD10
Mitochondrial protein degradation	1	57.1×	0.026	SPG7
Transport of small molecules	1	12.6×	0.094	SPG7
Metabolism of proteins	1	6.2×	0.155	SPG7

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
mitochondrial outer membrane permeabilization involved in programmed cell death	1	4213.0×	0.002	SPG7
regulation of calcium import into the mitochondrion	1	2808.7×	0.002	SPG7
mitochondrial protein processing	1	1404.3×	0.002	SPG7
mitochondrial membrane organization	1	1203.7×	0.002	CHCHD10
regulation of mitochondrial membrane permeability	1	702.2×	0.003	SPG7
inner mitochondrial membrane organization	1	421.3×	0.004	CHCHD10
anterograde axonal transport	1	290.6×	0.005	SPG7
mitochondrion organization	1	75.9×	0.016	CHCHD10
nervous system development	1	23.0×	0.048	SPG7
proteolysis	1	17.1×	0.058	SPG7

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CHCHD10	0	0
SPG7	0	0
C22orf15	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPG7	3.4.24.B18

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	SPG7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CHCHD10, C22orf15

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)
CHCHD10	0	—
SPG7	0	—
C22orf15	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.