Hereditary spastic paraplegia 77

Summary

Hereditary spastic paraplegia 77 (MONDO:0014882) is a disease caused by FARS2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FARS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0007020	Progressive spastic paraplegia	Obligate (100%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0010549	Weakness due to upper motor neuron dysfunction	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0012407	Scissor gait	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007210	Lower limb amyotrophy	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0003800	Muscle abnormality related to mitochondrial dysfunction	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000675	Macrodontia of permanent maxillary central incisor	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0005216	Impaired mastication	Occasional (5-29%)
HP:0002068	Neuromuscular dysphagia	Occasional (5-29%)
HP:0002882	Sudden episodic apnea	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0008110	Equinovarus deformity	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0008689	Bilateral cryptorchidism	Occasional (5-29%)
HP:0000011	Neurogenic bladder	Occasional (5-29%)
HP:0025488	Detrusor sphincter dyssynergia	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0100785	Insomnia	Occasional (5-29%)
HP:0002268	Paroxysmal dystonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 77
Mondo ID	MONDO:0014882
OMIM	617046
Orphanet	466722
DOID	DOID:0110822
UMLS	C5569007
MedGen	1800430
GARD	0017827
Is cancer (heuristic)	no

Also known as: FARS2 hereditary spastic paraplegia · hereditary spastic paraplegia caused by mutation in FARS2 · hereditary spastic paraplegia type 77 · spastic paraplegia 77, autosomal recessive · SPG77

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › hereditary spastic paraplegia 77

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

22 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 5 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
214335	NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214336	NM_006567.5(FARS2):c.1255C>T (p.Arg419Cys)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253159	NM_006567.5(FARS2):c.424G>T (p.Asp142Tyr)	FARS2	Pathogenic	criteria provided, single submitter
429663	NM_006567.5(FARS2):c.1256G>A (p.Arg419His)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
473309	NM_006567.5(FARS2):c.407C>A (p.Pro136His)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
579997	NM_006567.5(FARS2):c.792del (p.Asp265fs)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488357	NC_000006.11:g.5610223_5726369del	LOC101927950	Likely pathogenic	criteria provided, single submitter
488360	NM_006567.5(FARS2):c.461C>T (p.Ala154Val)	FARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587653	NM_006567.5(FARS2):c.476A>C (p.His159Pro)	FARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
640714	NM_006567.5(FARS2):c.1057A>C (p.Lys353Gln)	FARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473311	NM_006567.5(FARS2):c.497C>T (p.Ala166Val)	LOC126859565	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031655	NM_006567.5(FARS2):c.1004A>T (p.Glu335Val)	FARS2	Uncertain significance	criteria provided, single submitter
1449177	NM_006567.5(FARS2):c.515T>C (p.Leu172Pro)	FARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214340	NM_006567.5(FARS2):c.550G>A (p.Asp184Asn)	FARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2578453	NM_006567.5(FARS2):c.862G>C (p.Val288Leu)	FARS2	Uncertain significance	no assertion criteria provided
488362	NM_006567.5(FARS2):c.515TGG[2] (p.Val174del)	FARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
540536	NM_006567.5(FARS2):c.781A>T (p.Ile261Leu)	FARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
540539	NM_006567.5(FARS2):c.1009G>A (p.Glu337Lys)	FARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
545657	NM_006567.5(FARS2):c.422G>A (p.Gly141Glu)	FARS2	Uncertain significance	no assertion criteria provided
944163	NM_006567.5(FARS2):c.988C>T (p.Arg330Cys)	FARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1292064	NM_020408.6(LYRM4):c.-11_-10dup	FARS2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
137292	NM_006567.5(FARS2):c.839A>G (p.Asn280Ser)	FARS2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
FARS2	Strong	Autosomal recessive	hereditary spastic paraplegia 77	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FARS2	Orphanet:319519	Combined oxidative phosphorylation defect type 14
FARS2	Orphanet:466722	Autosomal recessive spastic paraplegia type 77

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
FARS2	HGNC:21062	ENSG00000145982	O95363	Phenylalanine–tRNA ligase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FARS2	Phenylalanine–tRNA ligase, mitochondrial	Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FARS2	Enzyme (other)	yes	6.1.1.20	Phenylalanyl-tRNA_Synthase, Phe-tRNA-synth_IIc_mito, Fdx_antiC-bd

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
endothelial cell	1
gluteal muscle	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FARS2	260	ubiquitous	marker	triceps brachii, endothelial cell, gluteal muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FARS2	2,506

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FARS2	O95363	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	FARS2
tRNA Aminoacylation	1	285.5×	0.007	FARS2
Translation	1	62.1×	0.021	FARS2
Metabolism of proteins	1	12.4×	0.081	FARS2

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
phenylalanyl-tRNA aminoacylation	1	4213.0×	7e-04	FARS2
tRNA aminoacylation for protein translation	1	842.6×	0.001	FARS2
tRNA processing	1	842.6×	0.001	FARS2

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
FARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FARS2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FARS2	6.1.1.20	phenylalanine-tRNA ligase

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	1	FARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FARS2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.