Hereditary spastic paraplegia 49

Summary

Hereditary spastic paraplegia 49 (MONDO:0014016) is a disease caused by TECPR2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TECPR2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,352
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0000248	Brachycephaly	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000294	Low anterior hairline	Frequent (30-79%)
HP:0000311	Round face	Frequent (30-79%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000475	Broad neck	Frequent (30-79%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002871	Central apnea	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 49
Mondo ID	MONDO:0014016
OMIM	615031
Orphanet	320385
DOID	DOID:0110801
UMLS	C3542549
MedGen	762260
GARD	0013568
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 49 · hereditary spastic paraplegia 49 · hereditary spastic paraplegia caused by mutation in TECPR2 · hereditary spastic paraplegia type 49 · neuropathy, hereditary sensory and autonomic, type IX, with developmental delay · spastic paraplegia 49, autosomal recessive · SPG49 · TECPR2 hereditary spastic paraplegia

Data availability: 1,352 ClinVar variants · 4 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 49

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 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, 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

600 retrieved; paginated sample, class counts are floors:

463 likely benign, 77 uncertain significance, 30 pathogenic, 10 likely pathogenic, 9 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 4 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065201	NM_014844.5(TECPR2):c.1318_1319del (p.Leu440fs)	TECPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071035	NM_014844.5(TECPR2):c.35_36del (p.Glu12fs)	TECPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071213	NM_014844.5(TECPR2):c.34G>T (p.Glu12Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1071450	NM_014844.5(TECPR2):c.1160_1161del (p.Thr387fs)	TECPR2	Pathogenic	criteria provided, single submitter
1072053	NM_014844.5(TECPR2):c.3326G>A (p.Trp1109Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1072318	NM_014844.5(TECPR2):c.2093G>A (p.Trp698Ter)	TECPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072374	NM_014844.5(TECPR2):c.3946C>T (p.Gln1316Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1072499	NM_014844.5(TECPR2):c.877del (p.Ser293fs)	TECPR2	Pathogenic	criteria provided, single submitter
1073499	NM_014844.5(TECPR2):c.2915G>A (p.Trp972Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1073977	NM_014844.5(TECPR2):c.3469_3470del (p.Gln1157fs)	TECPR2	Pathogenic	criteria provided, single submitter
1074322	NM_014844.5(TECPR2):c.2599G>T (p.Glu867Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1076042	NC_000014.8:g.(?102891306)(102901558_?)del	TECPR2	Pathogenic	criteria provided, single submitter
1339486	NM_014844.5(TECPR2):c.1751del (p.Gly584fs)	TECPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350644	NM_014844.5(TECPR2):c.1152del (p.Ala386fs)	TECPR2	Pathogenic	criteria provided, single submitter
1353644	NM_014844.5(TECPR2):c.25dup (p.Thr9fs)	TECPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356743	NM_014844.5(TECPR2):c.3686G>A (p.Trp1229Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1360096	NM_014844.5(TECPR2):c.3396del (p.Thr1133fs)	TECPR2	Pathogenic	criteria provided, single submitter
1375508	NM_014844.5(TECPR2):c.2988_2989del (p.Trp997fs)	TECPR2	Pathogenic	criteria provided, single submitter
1386551	NM_014844.5(TECPR2):c.675_676del (p.Leu225_Cys226insTer)	TECPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414294	NM_014844.5(TECPR2):c.3737_3738del (p.Leu1246fs)	TECPR2	Pathogenic	criteria provided, single submitter
1414575	NM_014844.5(TECPR2):c.1834_1835del (p.Gln612fs)	TECPR2	Pathogenic	criteria provided, single submitter
1451298	NC_000014.8:g.(?102894577)(102894729_?)del	TECPR2	Pathogenic	criteria provided, single submitter
1454429	NM_014844.4(TECPR2):c.222delG	TECPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458279	NM_014844.5(TECPR2):c.728G>A (p.Trp243Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1460289	NM_014844.5(TECPR2):c.3942del (p.Cys1315fs)	TECPR2	Pathogenic	criteria provided, single submitter
1924891	NM_014844.5(TECPR2):c.3918G>A (p.Trp1306Ter)	TECPR2	Pathogenic	criteria provided, single submitter
1943704	NM_014844.5(TECPR2):c.1470_1471insT (p.Glu491Ter)	TECPR2	Pathogenic	criteria provided, single submitter
2014529	NM_014844.5(TECPR2):c.3106C>T (p.Gln1036Ter)	TECPR2	Pathogenic	criteria provided, single submitter
2045726	NM_014844.5(TECPR2):c.2224C>T (p.Gln742Ter)	TECPR2	Pathogenic	criteria provided, single submitter
2061762	NM_014844.5(TECPR2):c.1083del (p.Thr361_Val362insTer)	TECPR2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TECPR2	Strong	Autosomal recessive	hereditary spastic paraplegia 49	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TECPR2	Orphanet:320385	Hereditary sensory and autonomic neuropathy due to TECPR2 mutation

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
TECPR2	HGNC:19957	ENSG00000196663	O15040	Tectonin beta-propeller repeat-containing protein 2	gencc,clinvar
ANKRD9	HGNC:20096	ENSG00000156381	Q96BM1	Ankyrin repeat domain-containing protein 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TECPR2	Tectonin beta-propeller repeat-containing protein 2	Probably plays a role as positive regulator of autophagy.
ANKRD9	Ankyrin repeat domain-containing protein 9	Substrate receptor subunit of a cullin-RING superfamily E3 ligase complex (CUL5-based E3 ubiquitin ligase complex) which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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
Scaffold/PPI	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TECPR2	Scaffold/PPI	no		WD40_rpt, Beta-propeller_rpt_TECPR, RCC1/BLIP-II
ANKRD9	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, E3_Ligase-Neurotoxin

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
inferior vagus X ganglion	1
lateral globus pallidus	1
secondary oocyte	1
pancreatic ductal cell	1
quadriceps femoris	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TECPR2	254	ubiquitous	marker	secondary oocyte, lateral globus pallidus, inferior vagus X ganglion
ANKRD9	256	ubiquitous	marker	pancreatic ductal cell, vastus lateralis, quadriceps femoris

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANKRD9	1,205
TECPR2	1,128

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD9	Q96BM1	82.45
TECPR2	O15040	68.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Neddylation	1	47.4×	0.063	ANKRD9
Post-translational protein modification	1	19.2×	0.078	ANKRD9
Metabolism of proteins	1	12.4×	0.081	ANKRD9

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
protein exit from endoplasmic reticulum	1	1053.2×	0.005	TECPR2
intracellular copper ion homeostasis	1	468.1×	0.005	ANKRD9
autophagy	1	55.1×	0.030	TECPR2
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.047	ANKRD9
protein ubiquitination	1	20.7×	0.048	ANKRD9

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
TECPR2	0	0
ANKRD9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	TECPR2, ANKRD9

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)
TECPR2	0	—
ANKRD9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.