Hereditary spastic paraplegia 57

Summary

Hereditary spastic paraplegia 57 (MONDO:0014295) is a disease caused by TFG (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TFG (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 379
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0003134	Abnormality of peripheral nerve conduction	Obligate (100%)
HP:0003551	Difficulty climbing stairs	Obligate (100%)
HP:0003698	Difficulty standing	Obligate (100%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0002540	Inability to walk	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0005109	Abnormality of the Achilles tendon	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0007178	Motor polyneuropathy	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0012447	Abnormal myelination	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 57
Mondo ID	MONDO:0014295
OMIM	615658
Orphanet	431329
DOID	DOID:0110809
SNOMED CT	723826007
UMLS	C3714897
MedGen	811490
GARD	0017712
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 57 · hereditary spastic paraplegia caused by mutation in TFG · hereditary spastic paraplegia type 57 · spastic paraplegia 57, autosomal recessive · spastic paraplegia due to partial TFG deficiency · SPG57 · TFG hereditary spastic paraplegia

Data availability: 379 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 57

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

379 retrieved; paginated sample, class counts are floors:

194 uncertain significance, 154 likely benign, 12 benign, 10 conflicting classifications of pathogenicity, 5 benign/likely benign, 2 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100909	NM_006070.6(TFG):c.316C>T (p.Arg106Cys)	TFG	Pathogenic	criteria provided, multiple submitters, no conflicts
1452866	NM_006070.6(TFG):c.64C>T (p.Arg22Trp)	TFG	Pathogenic	criteria provided, multiple submitters, no conflicts
156445	NM_006070.6(TFG):c.806G>T (p.Gly269Val)	TFG	Pathogenic/Likely pathogenic	no assertion criteria provided
37089	NM_006070.6(TFG):c.854C>T (p.Pro285Leu)	TFG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1039628	NM_006070.6(TFG):c.738G>C (p.Gln246His)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1075540	NM_006070.6(TFG):c.317G>A (p.Arg106His)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1907305	NM_006070.6(TFG):c.968A>G (p.Asn323Ser)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1986386	NM_006070.6(TFG):c.325C>T (p.Leu109=)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245772	NM_006070.6(TFG):c.1060C>G (p.Pro354Ala)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
466412	NM_006070.6(TFG):c.988A>G (p.Thr330Ala)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
581201	NM_006070.6(TFG):c.1199G>A (p.Arg400Gln)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
582975	NM_006070.6(TFG):c.310T>C (p.Tyr104His)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706581	NM_006070.6(TFG):c.1048G>A (p.Ala350Thr)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
779515	NM_006070.6(TFG):c.771G>A (p.Gln257=)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003573	NM_006070.6(TFG):c.373C>T (p.Pro125Ser)	TFG	Uncertain significance	criteria provided, single submitter
1004051	NM_006070.6(TFG):c.198A>G (p.Ile66Met)	TFG	Uncertain significance	criteria provided, single submitter
1009525	NM_006070.6(TFG):c.9_10delinsGA (p.Gln4Lys)	TFG	Uncertain significance	criteria provided, single submitter
1011451	NM_006070.6(TFG):c.353G>A (p.Arg118His)	TFG	Uncertain significance	criteria provided, single submitter
1019608	NM_006070.6(TFG):c.986dup (p.Tyr329Ter)	TFG	Uncertain significance	criteria provided, single submitter
1019766	NM_006070.6(TFG):c.820+3G>A	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025286	NM_006070.6(TFG):c.850C>G (p.Gln284Glu)	TFG	Uncertain significance	criteria provided, single submitter
1030071	NM_006070.6(TFG):c.320G>C (p.Arg107Pro)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1035040	NM_006070.6(TFG):c.61A>T (p.Ile21Phe)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1051770	NM_006070.6(TFG):c.1163T>G (p.Phe388Cys)	TFG	Uncertain significance	criteria provided, single submitter
1052695	NM_006070.6(TFG):c.622G>A (p.Asp208Asn)	TFG	Uncertain significance	criteria provided, single submitter
1054786	NM_006070.6(TFG):c.34A>G (p.Ile12Val)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1062624	NC_000003.11:g.(?100455410)(100463785_?)del	TFG	Uncertain significance	criteria provided, single submitter
1063471	NM_006070.6(TFG):c.499G>A (p.Ala167Thr)	TFG	Uncertain significance	criteria provided, single submitter
1313772	NM_006070.6(TFG):c.1147C>T (p.Arg383Cys)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1358338	NM_006070.6(TFG):c.293A>C (p.Glu98Ala)	TFG	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
TFG	Strong	Autosomal recessive	hereditary spastic paraplegia 57	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TFG	Orphanet:146	Differentiated thyroid carcinoma
TFG	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
TFG	Orphanet:431329	Autosomal recessive spastic paraplegia type 57
TFG	Orphanet:435819	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation
TFG	Orphanet:90117	Hereditary motor and sensory neuropathy, Okinawa type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TFG	HGNC:11758	ENSG00000114354	Q92734	Protein TFG	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TFG	Protein TFG	Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TFG	Other/Unknown	no		PB1_dom, TFG, PB1_TFG

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingival epithelium	1
jejunal mucosa	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TFG	288	ubiquitous	marker	secondary oocyte, jejunal mucosa, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TFG	674

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TFG	Q92734	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 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
Signaling by ALK in cancer	1	271.9×	0.023	TFG
COPII-mediated vesicle transport	1	163.1×	0.023	TFG
Signaling by ALK fusions and activated point mutants	1	150.3×	0.023	TFG
ER to Golgi Anterograde Transport	1	132.8×	0.023	TFG
Transport to the Golgi and subsequent modification	1	102.9×	0.023	TFG
Asparagine N-linked glycosylation	1	60.1×	0.030	TFG
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.030	TFG
Membrane Trafficking	1	37.1×	0.038	TFG
Vesicle-mediated transport	1	34.8×	0.038	TFG
Post-translational protein modification	1	19.2×	0.063	TFG
Disease	1	13.1×	0.081	TFG
Metabolism of proteins	1	12.4×	0.081	TFG

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
COPII vesicle coat assembly	1	702.2×	0.004	TFG
endoplasmic reticulum to Golgi vesicle-mediated transport	1	135.9×	0.011	TFG
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.014	TFG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
TFG	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
TFG	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TFG

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)
TFG	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.