RTN2

Summary

RTN2 (reticulon 2, HGNC:10468) is a protein-coding gene on chromosome 19q13.32, encoding Reticulon-2 (O75298). Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity.

This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Reticulon proteins also play an important role in the replication of positive-strand RNA (ssRNA) viruses. Mutations at this locus have been associated with autosomal dominant spastic paraplegia-12.

Source: NCBI Gene 6253 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 348 total — 8 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 56
• MANE Select transcript: NM_005619

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10468
Approved symbol	RTN2
Name	reticulon 2
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	NSP2, NSPL1
Ensembl gene	ENSG00000125744
Ensembl biotype	protein_coding
OMIM	603183
Entrez	6253

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 5 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000245923, ENST00000344680, ENST00000430715, ENST00000587597, ENST00000588036, ENST00000589384, ENST00000589628, ENST00000590526, ENST00000590746, ENST00000591286, ENST00000591789, ENST00000592064, ENST00000593129, ENST00000593187, ENST00000920224

RefSeq mRNA: 3 — MANE Select: NM_005619 NM_005619, NM_206900, NM_206901

CCDS: CCDS12665, CCDS12666, CCDS46114

Canonical transcript exons

ENST00000245923 — 11 exons

Exon	Start	End
ENSE00002896175	45496792	45497047
ENSE00003480407	45488637	45488706
ENSE00003480495	45493160	45493378
ENSE00003522477	45485294	45485789
ENSE00003525689	45486055	45486113
ENSE00003586929	45494166	45494420
ENSE00003601531	45488471	45488517
ENSE00003602846	45494526	45495005
ENSE00003608097	45488848	45488986
ENSE00003645358	45495095	45495139
ENSE00003659320	45489346	45489553

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9655 / max 369.5634, expressed in 1708 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181528	9.2892	1497
181530	2.2901	1055
181531	0.2543	117
181529	0.1319	58

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.93	gold quality
gastrocnemius	UBERON:0001388	98.66	gold quality
vastus lateralis	UBERON:0001379	98.62	gold quality
quadriceps femoris	UBERON:0001377	98.61	gold quality
diaphragm	UBERON:0001103	98.51	gold quality
skeletal muscle tissue	UBERON:0001134	98.28	gold quality
triceps brachii	UBERON:0001509	98.27	gold quality
biceps brachii	UBERON:0001507	98.15	gold quality
gluteal muscle	UBERON:0002000	98.02	gold quality
muscle organ	UBERON:0001630	97.81	gold quality
skeletal muscle organ	UBERON:0014892	97.81	gold quality
body of tongue	UBERON:0011876	97.74	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.70	gold quality
deltoid	UBERON:0001476	97.59	gold quality
muscle of leg	UBERON:0001383	97.55	gold quality
tibialis anterior	UBERON:0001385	97.31	gold quality
cortical plate	UBERON:0005343	96.58	gold quality
muscle tissue	UBERON:0002385	95.34	gold quality
right frontal lobe	UBERON:0002810	94.41	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.91	gold quality
dorsal root ganglion	UBERON:0000044	93.40	gold quality
tongue	UBERON:0001723	93.00	gold quality
cingulate cortex	UBERON:0003027	92.79	gold quality
anterior cingulate cortex	UBERON:0009835	92.74	gold quality
frontal pole	UBERON:0002795	92.42	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.22	gold quality
ganglionic eminence	UBERON:0004023	92.12	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.19
E-MTAB-7606	no	16.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting RTN2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-605-5P	98.79	68.24	1161
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-3690	96.44	65.18	737
HSA-MIR-2114-5P	96.00	64.56	617
HSA-MIR-635	96.00	65.54	687
HSA-MIR-6774-5P	95.94	65.18	722

Literature-anchored findings (GeneRIF, showing 7)

• RTN2B functions as a positive regulator in the delivery of EAAC1 from the ER to the cell surface. (PMID:18096700)
• sk-NSPl1 is a novel dantrolene receptor that plays an important role in membrane translocation of GLUT4 induced by contraction/exercise. The 23-kDa sk-NSPl1 may also be involved in the regulation of glucose levels in the whole body. (PMID:19720795)
• Results implicate reticulon 2 in axonopathy, show that this protein participates in a network of interactions among hereditary spastic paraplegia proteins involved in endoplasmic reticulum shaping. (PMID:22232211)
• New phenotype of RTN2-related spectrum: Complicated form of spastic paraplegia-12. (PMID:35684947)
• RTN2, a new member of circadian clock genes identified by database mining and bioinformatics prediction, is highly expressed in ovarian cancer. (PMID:36177918)
• O-GlcNAcylation enhances Reticulon 2 protein stability and its promotive effects on gastric cancer progression. (PMID:37196774)
• Discusses cloning of mouse neuroendocrine-specific protein-like 1, in addition to partial cloning of the human ortholog. Also studies expression of both the mouse and human genes. (PMID:9530622)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtn2b	ENSDARG00000057027
mus_musculus	Rtn2	ENSMUSG00000030401
rattus_norvegicus	Rtn2	ENSRNOG00000016603
drosophila_melanogaster	Rtnl2	FBGN0015831
drosophila_melanogaster	Rtnl1	FBGN0053113

Paralogs (4): RTN4 (ENSG00000115310), RTN3 (ENSG00000133318), RTN1 (ENSG00000139970), PRR18 (ENSG00000176381)

Protein

Protein identifiers

Reticulon-2 — O75298 (reviewed: O75298)

Alternative names: Neuroendocrine-specific protein-like 1, Neuroendocrine-specific protein-like I

All UniProt accessions (4): O75298, K7EMR7, Q7RTN0, Q96CG9

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity. Enhances trafficking of the glutamate transporter SLC1A1/EAAC1 from the endoplasmic reticulum to the cell surface. Plays a role in the translocation of SLC2A4/GLUT4 from intracellular membranes to the cell membrane which facilitates the uptake of glucose into the cell.

Subunit / interactions. Interacts with isoform 1 but not isoform 3 of SPAST. Interacts with BACE1. Interacts (via first transmembrane domain) with ARL6IP5/GTRAP3-18. Interacts (via N-terminus) with SLC1A1/EAAC1; the interaction promotes cell surface expression of SLC1A1. Interacts with TMEM33.

Subcellular location. Endoplasmic reticulum membrane. Sarcoplasmic reticulum membrane. Cell membrane. Sarcolemma. T-tubule. Cytoplasm. Myofibril. Sarcomere. Z line. Cytoskeleton.

Tissue specificity. Highly expressed in skeletal muscle.

Disease relevance. Spastic paraplegia 12, autosomal dominant (SPG12) [MIM:604805] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity (HMNR11) [MIM:620854] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. HMNR11 is an autosomal recessive form characterized by slowly progressive muscle weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Affected individuals have difficulty walking, although ambulation is retained into adulthood. Nerve conduction studies reveal axonal motor neuropathy with neurogenic changes in the electromyography. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Produced by alternative initiation at Met-341 of isoform RTN2-A.

Isoforms (3)

UniProt ID	Names	Canonical?
O75298-1	RTN2-A	yes
O75298-2	RTN2-B
O75298-3	RTN2-C

RefSeq proteins (3): NP_005610, NP_996783, NP_996784 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003388	Reticulon	Domain
IPR046964	RTN1-4	Family

Pfam: PF02453

UniProt features (24 total): sequence variant 8, compositionally biased region 5, modified residue 3, transmembrane region 2, splice variant 2, region of interest 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75298-F1	50.99	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 44, 227, 229

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 273 (showing top): GOBP_CARBOHYDRATE_TRANSPORT, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCACTT_MIR519C_MIR519B_MIR519A, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GOBP_NEGATIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, COUP_01, PATIL_LIVER_CANCER, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, GOBP_REGULATION_OF_AMYLOID_PRECURSOR_PROTEIN_CATABOLIC_PROCESS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_D_GLUCOSE_IMPORT

GO Biological Process (9): brain development (GO:0007420), gene expression (GO:0010467), neuron differentiation (GO:0030182), regulation of D-glucose import across plasma membrane (GO:0046324), intracellular protein transmembrane transport (GO:0065002), endoplasmic reticulum tubular network formation (GO:0071787), negative regulation of amyloid-beta formation (GO:1902430), endoplasmic reticulum tubular network membrane organization (GO:1990809), protein transport (GO:0015031)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (16): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), intermediate filament (GO:0005882), cell surface (GO:0009986), postsynaptic density (GO:0014069), terminal cisterna (GO:0014802), Z disc (GO:0030018), T-tubule (GO:0030315), sarcoplasmic reticulum membrane (GO:0033017), neuron projection (GO:0043005), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), sarcolemma (GO:0042383)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
endoplasmic reticulum tubular network organization	2
endoplasmic reticulum subcompartment	2
sarcoplasmic reticulum	2
central nervous system development	1
animal organ development	1
head development	1
macromolecule biosynthetic process	1
cell differentiation	1
generation of neurons	1
regulation of D-glucose transmembrane transport	1
D-glucose import across plasma membrane	1
intracellular protein transport	1
protein transmembrane transport	1
cellular component assembly	1
amyloid-beta formation	1
regulation of amyloid-beta formation	1
negative regulation of amyloid precursor protein catabolic process	1
endoplasmic reticulum membrane organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1
asymmetric synapse	1
postsynaptic specialization	1
I band	1
sarcolemma	1
endoplasmic reticulum membrane	1
bounding membrane of organelle	1
plasma membrane bounded cell projection	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
membrane	1

Protein interactions and networks

STRING

1234 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTN2	ATL1	Q8WXF7	838
RTN2	REEP5	Q00765	824
RTN2	SPAST	Q9UBP0	810
RTN2	REEP1	Q9H902	750
RTN2	REEP2	Q9BRK0	734
RTN2	BACE1	P56817	706
RTN2	ATL3	Q6DD88	688
RTN2	RTN1	Q16799	687
RTN2	NUS1	Q96E22	676
RTN2	ATL2	Q8NHH9	671
RTN2	NIPA1	Q7RTP0	619
RTN2	BSCL2	Q96G97	613
RTN2	ARL6IP1	Q15041	587
RTN2	WASHC5	Q12768	582
RTN2	AP5Z1	O43299	578

IntAct

42 interactions, top by confidence:

A	B	Type	Score
RTN2	RTN4	psi-mi:“MI:0915”(physical association)	0.620
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
GYPB	TCAF2	psi-mi:“MI:0914”(association)	0.530
TMEM31	PSMD11	psi-mi:“MI:0914”(association)	0.530
FAM241A	NRP1	psi-mi:“MI:0914”(association)	0.530
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
FAM241A	SPTLC2	psi-mi:“MI:0914”(association)	0.530
	FAM171A2	psi-mi:“MI:0914”(association)	0.350
COPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
RTN4	ESYT2	psi-mi:“MI:0914”(association)	0.350
VAPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
RTN1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TNFSF18	TMEM120B	psi-mi:“MI:0914”(association)	0.350
C11orf87	KLRG2	psi-mi:“MI:0914”(association)	0.350
TSPAN10	KLRG2	psi-mi:“MI:0914”(association)	0.350
FPR2	GPR89A	psi-mi:“MI:0914”(association)	0.350
TMEM169	GPR89A	psi-mi:“MI:0914”(association)	0.350
MALL	GPR89A	psi-mi:“MI:0914”(association)	0.350
NAT8B	COX7A2L	psi-mi:“MI:0914”(association)	0.350
RTN4	SCAMP1	psi-mi:“MI:0914”(association)	0.350
TMEM128	PLSCR1	psi-mi:“MI:0914”(association)	0.350
CD63	ABCC4	psi-mi:“MI:0914”(association)	0.350
ATP1B4	SYNGR3	psi-mi:“MI:0914”(association)	0.350
SFT2D1	TSPAN3	psi-mi:“MI:0914”(association)	0.350
LDAF1	SLC19A2	psi-mi:“MI:0914”(association)	0.350
GP5	SLC19A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (67): RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS), JPH1 (Affinity Capture-MS), MCRS1 (Affinity Capture-MS), TNKS (Affinity Capture-MS), RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS), RTN2 (Synthetic Lethality), RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS), RTN2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GU29, A2A9F4, A2ANU3, A4IFJ1, A6NDD5, A6NMD0, M3WHG5, O75298, Q08DM6, Q32M26, Q3USQ7, Q4R532, Q58DZ9, Q5BK39, Q63247, Q64322, Q68DV7, Q6AY88, Q6KAU7, Q6NUJ2, Q6ZNR0, Q76N89, Q76NI1, Q8BLR5, Q8BP99, Q8BR26, Q8BWG4, Q8BZW2, Q8C581, Q8C708, Q8IUC6, Q8IXW0, Q8K0W3, Q8NAX2, Q8NC06, Q8NDX1, Q8R2H3, Q8VIM4, Q8WV48, Q8WWG9

Diamond homologs: A7MC64, O70622, O75298, O95197, Q08D83, Q16799, Q28D16, Q4FZ58, Q4FZ76, Q5IS59, Q5J6M8, Q5MY90, Q5RBL9, Q64548, Q68EW1, Q6IFY7, Q6RJR6, Q6WN19, Q8K0T0, Q99P72, Q9ES97, Q9JK11, Q9NQC3, Q6NPD8, Q9SH59

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TRIM4	“down-regulates quantity”	RTN2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

348 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	5
Uncertain significance	178
Likely benign	88
Benign	25

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1073870	NM_005619.5(RTN2):c.1167C>A (p.Cys389Ter)	Pathogenic
30324	NM_005619.5(RTN2):c.178dup (p.Arg60fs)	Pathogenic
30325	NC_000019.10:g.(?45485294_45497047?)del	Pathogenic
3248640	NM_005619.5(RTN2):c.103C>T (p.Arg35Ter)	Pathogenic
3248641	NM_005619.5(RTN2):c.287del (p.Pro96fs)	Pathogenic
3248642	NM_005619.5(RTN2):c.701_702dup (p.Leu235fs)	Pathogenic
3248643	NM_005619.5(RTN2):c.79G>T (p.Gly27Ter)	Pathogenic
4765781	NM_005619.5(RTN2):c.831G>A (p.Trp277Ter)	Pathogenic
1474923	NM_005619.5(RTN2):c.1380+1G>T	Likely pathogenic
2683111	NM_005619.5(RTN2):c.1154del (p.Leu385fs)	Likely pathogenic
623958	NM_005619.5(RTN2):c.265C>T (p.Gln89Ter)	Likely pathogenic
808601	NM_005619.5(RTN2):c.37G>T (p.Glu13Ter)	Likely pathogenic
994450	NM_005619.5(RTN2):c.1497+2T>C	Likely pathogenic

SpliceAI

1683 predictions. Top by Δscore:

Variant	Effect	Δscore
19:45486053:A:AC	donor_gain	1.0000
19:45486054:C:CC	donor_gain	1.0000
19:45486054:CTTAG:C	donor_gain	1.0000
19:45486057:A:AC	donor_gain	1.0000
19:45486058:G:C	donor_gain	1.0000
19:45486114:C:CA	acceptor_loss	1.0000
19:45486124:C:CT	acceptor_gain	1.0000
19:45486125:A:T	acceptor_gain	1.0000
19:45488466:CTCA:C	donor_loss	1.0000
19:45488467:TCA:T	donor_loss	1.0000
19:45488513:CACTC:C	acceptor_gain	1.0000
19:45488515:CTC:C	acceptor_gain	1.0000
19:45488516:TCC:T	acceptor_loss	1.0000
19:45488518:C:CC	acceptor_gain	1.0000
19:45488518:CT:C	acceptor_loss	1.0000
19:45488519:T:A	acceptor_loss	1.0000
19:45488985:CC:C	acceptor_gain	1.0000
19:45488986:CC:C	acceptor_gain	1.0000
19:45488986:CCT:C	acceptor_loss	1.0000
19:45488988:T:G	acceptor_loss	1.0000
19:45489344:A:AC	donor_gain	1.0000
19:45489345:C:CC	donor_gain	1.0000
19:45495003:CTC:C	acceptor_gain	1.0000
19:45495005:CCTGC:C	acceptor_loss	1.0000
19:45495006:CTGCA:C	acceptor_loss	1.0000
19:45495091:TTACC:T	donor_loss	1.0000
19:45495092:TAC:T	donor_loss	1.0000
19:45495094:C:CA	donor_loss	1.0000
19:45495094:CCTT:C	donor_gain	1.0000
19:45495140:C:CC	acceptor_gain	1.0000

AlphaMissense

3440 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:45489534:C:A	W351C	0.998
19:45489534:C:G	W351C	0.998
19:45489462:G:C	S375R	0.997
19:45489462:G:T	S375R	0.997
19:45489464:T:G	S375R	0.997
19:45489536:A:G	W351R	0.997
19:45489536:A:T	W351R	0.997
19:45488501:G:C	F489L	0.996
19:45488501:G:T	F489L	0.996
19:45488503:A:G	F489L	0.996
19:45486106:A:T	I502N	0.994
19:45496802:G:C	F8L	0.994
19:45496802:G:T	F8L	0.994
19:45496804:A:G	F8L	0.994
19:45489463:C:A	S375I	0.993
19:45489479:A:G	C370R	0.993
19:45494893:G:C	F64L	0.993
19:45494893:G:T	F64L	0.993
19:45494895:A:G	F64L	0.993
19:45485787:A:G	I520T	0.991
19:45488485:A:C	Y495D	0.991
19:45488493:G:C	P492R	0.991
19:45488493:G:T	P492H	0.991
19:45488637:C:G	G484R	0.991
19:45488637:C:T	G484R	0.991
19:45488673:C:G	G472R	0.991
19:45489535:C:G	W351S	0.991
19:45486106:A:C	I502S	0.990
19:45488502:A:G	F489S	0.990
19:45486085:A:T	V509E	0.989

dbSNP variants (sampled 300 via entrez): RS1000356451 (19:45488905 C>T), RS1000458460 (19:45494886 T>C), RS1000542095 (19:45485058 C>G), RS1000963218 (19:45490222 G>A), RS1001288296 (19:45494059 T>C,G), RS1001327501 (19:45488383 A>G,T), RS1001395656 (19:45488326 A>G), RS1001444720 (19:45488495 G>A,T), RS1001747849 (19:45488183 A>C), RS1002301521 (19:45496325 C>T), RS1002345698 (19:45489686 T>TC), RS1002449386 (19:45489857 T>G), RS1002698424 (19:45495939 A>G), RS1002786965 (19:45489931 C>T), RS1004077083 (19:45496554 A>G)

Disease associations

OMIM: gene MIM:603183 | disease phenotypes: MIM:604805, MIM:303350, MIM:620854

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity	Strong	Autosomal recessive
hereditary spastic paraplegia 12	Strong	Autosomal dominant

Mondo (3): hereditary spastic paraplegia 12 (MONDO:0011489), hereditary spastic paraplegia (MONDO:0019064), neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity (MONDO:0971150)

Orphanet (2): Autosomal dominant spastic paraplegia type 12 (Orphanet:100993), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001258	Spastic paraplegia
HP:0001270	Motor delay
HP:0001283	Bulbar palsy
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0001763	Pes planus
HP:0001765	Hammertoe
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002070	Limb ataxia
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002169	Clonus
HP:0002314	Degeneration of the lateral corticospinal tracts
HP:0002345	Action tremor
HP:0002359	Frequent falls
HP:0002607	Bowel incontinence
HP:0002839	Urinary bladder sphincter dysfunction
HP:0002921	Abnormal cerebrospinal fluid morphology
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003307	Hyperlordosis
HP:0003394	Muscle spasm
HP:0003438	Absent Achilles reflex
HP:0003457	EMG abnormality

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003075_43	Cognitive decline rate in late mild cognitive impairment	8.000000e-07
GCST003075_61	Cognitive decline rate in late mild cognitive impairment	2.000000e-06
GCST007827_3	Alzheimer’s disease or HDL levels (pleiotropy)	1.000000e-97

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C537484	Spastic paraplegia 12, autosomal dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
Benzo(a)pyrene	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	increases expression	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	decreases expression	1
Coumestrol	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	decreases expression	1

Clinical trials (associated diseases)

51 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury
NCT05613114	Not specified	COMPLETED	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia
NCT05767268	Not specified	COMPLETED	Assessment of the Psychophysical State During Rehabilitation Treatment With Lokomat
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies
NCT06573866	Not specified	RECRUITING	Enhancement of Quality of Work And Life
NCT06680063	Not specified	COMPLETED	Correlation Between Clinical Assessment and Neurophysiological Assessment in Spinal Cord Injury