REEP2

Summary

REEP2 (receptor accessory protein 2, HGNC:17975) is a protein-coding gene on chromosome 5q31.2, encoding Receptor expression-enhancing protein 2 (Q9BRK0). Required for endoplasmic reticulum (ER) network formation, shaping and remodeling.

This gene encodes a member of the receptor expression enhancing protein family. Studies of a related gene in mouse suggest that the encoded protein is found in the cell membrane and enhances the function of sweet taste receptors. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51308 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 72 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 152 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 27
• MANE Select transcript: NM_001271803

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17975
Approved symbol	REEP2
Name	receptor accessory protein 2
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Aliases	SGC32445, SPG72, Yip2d
Ensembl gene	ENSG00000132563
Ensembl biotype	protein_coding
OMIM	609347
Entrez	51308

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 10 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000254901, ENST00000378339, ENST00000464751, ENST00000503379, ENST00000504163, ENST00000506158, ENST00000507511, ENST00000507635, ENST00000510467, ENST00000512126, ENST00000903313, ENST00000903314, ENST00000903315, ENST00000917402, ENST00000917403, ENST00000917404

RefSeq mRNA: 2 — MANE Select: NM_001271803 NM_001271803, NM_016606

CCDS: CCDS4205, CCDS64259

Canonical transcript exons

ENST00000378339 — 8 exons

Exon	Start	End
ENSE00001129340	138439057	138439240
ENSE00001320042	138445683	138446965
ENSE00003485891	138441016	138441088
ENSE00003560983	138445228	138445375
ENSE00003586192	138441385	138441461
ENSE00003655423	138445468	138445598
ENSE00003662584	138444415	138444535
ENSE00003678640	138444754	138444867

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1360 / max 320.0471, expressed in 1289 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58763	13.1064	1276
58762	0.4220	249
203705	0.4134	153
58764	0.1712	95
203704	0.0230	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.02	gold quality
cerebellar hemisphere	UBERON:0002245	98.91	gold quality
cerebellar cortex	UBERON:0002129	98.86	gold quality
right frontal lobe	UBERON:0002810	98.53	gold quality
cerebellum	UBERON:0002037	97.79	gold quality
cortical plate	UBERON:0005343	97.59	gold quality
cingulate cortex	UBERON:0003027	97.44	gold quality
anterior cingulate cortex	UBERON:0009835	97.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.38	gold quality
nucleus accumbens	UBERON:0001882	97.07	gold quality
prefrontal cortex	UBERON:0000451	96.98	gold quality
amygdala	UBERON:0001876	96.78	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.40	gold quality
adenohypophysis	UBERON:0002196	96.18	gold quality
putamen	UBERON:0001874	96.11	gold quality
caudate nucleus	UBERON:0001873	96.02	gold quality
neocortex	UBERON:0001950	95.80	gold quality
frontal cortex	UBERON:0001870	95.74	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.68	gold quality
hypothalamus	UBERON:0001898	95.51	gold quality
pituitary gland	UBERON:0000007	95.28	gold quality
telencephalon	UBERON:0001893	94.98	gold quality
brain	UBERON:0000955	94.97	gold quality
forebrain	UBERON:0001890	94.94	gold quality
cerebral cortex	UBERON:0000956	94.88	gold quality
central nervous system	UBERON:0001017	94.84	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.47	gold quality
ganglionic eminence	UBERON:0004023	94.11	gold quality
Ammon’s horn	UBERON:0001954	93.98	gold quality
substantia nigra	UBERON:0002038	93.45	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-70580	no	10.77
E-ANND-3	no	1.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting REEP2, 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-4283	100.00	66.42	2097
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-4483	98.09	64.12	1642

Literature-anchored findings (GeneRIF, showing 4)

• In mouse, Reep2 enhances sweet receptor function by a different mechanism than Reep1 uses to enhance olfactory receptor function. (PMID:20943918)
• Expression of the REEP1/REEP2 subfamily appears to be restricted to neuronal and neuronal-like exocytotic tissues, consistent with neuronally restricted symptoms of REEP1 genetic disorders. (PMID:24355597)
• We have identified mutations in REEP2 in two families with relatively pure, early-onset hereditary spastic paraplegia, one with autosomal-dominant and the other with autosomal-recessive transmission. (PMID:24388663)
• A Nepalese family with an REEP2 mutation: clinical and genetic study. (PMID:33526816)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	reep2	ENSDARG00000031382
mus_musculus	Reep2	ENSMUSG00000038555
rattus_norvegicus	Reep2	ENSRNOG00000049629
drosophila_melanogaster	Reepl1	FBGN0030313
drosophila_melanogaster	CG5539	FBGN0034907
caenorhabditis_elegans		WBGENE00011401
caenorhabditis_elegans		WBGENE00012180
caenorhabditis_elegans		WBGENE00018930
caenorhabditis_elegans		WBGENE00020562
caenorhabditis_elegans	yop-1	WBGENE00022127

Paralogs (5): REEP1 (ENSG00000068615), REEP6 (ENSG00000115255), REEP5 (ENSG00000129625), REEP3 (ENSG00000165476), REEP4 (ENSG00000168476)

Protein

Protein identifiers

Receptor expression-enhancing protein 2 — Q9BRK0 (reviewed: Q9BRK0)

All UniProt accessions (5): Q9BRK0, A8K3D2, B4DE60, D6RB42, H0YAC5

UniProt curated annotations — full annotation on UniProt →

Function. Required for endoplasmic reticulum (ER) network formation, shaping and remodeling. May enhance the cell surface expression of odorant receptors.

Subunit / interactions. Interacts with odorant receptor proteins.

Subcellular location. Membrane.

Tissue specificity. Detected in brain, heart and skeletal muscle, and at low levels in placenta, kidney and pancreas. Expressed in circumvallate papillae.

Disease relevance. Spastic paraplegia 72A, autosomal dominant (SPG72A) [MIM:615625] 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. SPG72A is a pure form of spastic paraplegia with onset of difficulty walking and stiff legs associated with hyperreflexia and extensor plantar responses in early childhood. Some patients may have pes cavus or sphincter disturbances. Cognition, speech, and ocular function are normal. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 72B, autosomal recessive (SPG72B) [MIM:620606] 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. SPG72B is a pure form of spastic paraplegia with onset of difficulty walking and stiff legs associated with hyperreflexia and extensor plantar responses in early childhood. Cognition, speech, and ocular function are normal. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DP1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BRK0-1	1	yes
Q9BRK0-2	2

RefSeq proteins (2): NP_001258732, NP_057690 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004345	TB2_DP1_HVA22	Family

Pfam: PF03134

UniProt features (9 total): transmembrane region 2, sequence variant 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRK0-F1	65.05	0.09

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 (1): 150

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 162 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_SENSORY_PERCEPTION_OF_TASTE, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_SENSORY_PERCEPTION, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOBP_MEMBRANE_ORGANIZATION, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_LOCALIZATION_WITHIN_MEMBRANE, SHEN_SMARCA2_TARGETS_DN, GOCC_ENDOPLASMIC_RETICULUM_TUBULAR_NETWORK, chr5q31, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK

GO Biological Process (4): protein transport into membrane raft (GO:0032596), sensory perception of bitter taste (GO:0050913), sensory perception of sweet taste (GO:0050916), endoplasmic reticulum tubular network organization (GO:0071786)

GO Molecular Function (3): microtubule binding (GO:0008017), taste receptor binding (GO:0031883), protein binding (GO:0005515)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytoplasmic microtubule (GO:0005881), plasma membrane (GO:0005886), endoplasmic reticulum tubular network (GO:0071782), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of taste	2
cytoplasm	2
endoplasmic reticulum subcompartment	2
protein transport within lipid bilayer	1
establishment of protein localization to membrane	1
protein localization to membrane raft	1
endoplasmic reticulum organization	1
tubulin binding	1
G protein-coupled receptor binding	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
microtubule	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

746 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
REEP2	ATL1	Q8WXF7	735
REEP2	RTN2	O75298	734
REEP2	RAB3GAP2	Q9H2M9	687
REEP2	SPAST	Q9UBP0	668
REEP2	ATL3	Q6DD88	664
REEP2	ARL6IP1	Q15041	614
REEP2	TECPR2	O15040	575
REEP2	ATL2	Q8NHH9	573
REEP2	MTRFR	Q9H3J6	570
REEP2	ZFYVE26	Q68DK2	567
REEP2	ZFYVE27	Q5T4F4	567
REEP2	NIPA1	Q7RTP0	566
REEP2	AP5Z1	O43299	564
REEP2	SPG11	Q96JI7	555
REEP2	ERLIN2	O94905	546

IntAct

102 interactions, top by confidence:

A	B	Type	Score
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
SLC16A4	REEP2	psi-mi:“MI:0915”(physical association)	0.560
TMEM42	REEP2	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	REEP2	psi-mi:“MI:0915”(physical association)	0.560
TMEM120B	REEP2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	REEP2	psi-mi:“MI:0915”(physical association)	0.560
NAT8	REEP2	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	REEP2	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	REEP2	psi-mi:“MI:0915”(physical association)	0.560
CYP4F2	REEP2	psi-mi:“MI:0915”(physical association)	0.560
TMEM239	REEP2	psi-mi:“MI:0915”(physical association)	0.560
RABAC1	REEP2	psi-mi:“MI:0915”(physical association)	0.560
YIF1A	REEP2	psi-mi:“MI:0915”(physical association)	0.560
BNIP3	REEP2	psi-mi:“MI:0915”(physical association)	0.560
SLC25A46	REEP2	psi-mi:“MI:0915”(physical association)	0.560
	REEP2	psi-mi:“MI:0915”(physical association)	0.560
ITGAM	REEP2	psi-mi:“MI:0915”(physical association)	0.560
SCD	REEP2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (89): REEP2 (Proximity Label-MS), REEP2 (Proximity Label-MS), REEP2 (Affinity Capture-MS), KCNIP2 (Affinity Capture-MS), REEP2 (Affinity Capture-MS), DSG4 (Affinity Capture-MS), REEP2 (Proximity Label-MS), REEP2 (Two-hybrid), REEP2 (Two-hybrid), REEP2 (Two-hybrid), TMEM60 (Two-hybrid), TTPA (Two-hybrid), TMBIM6 (Two-hybrid), NAT8 (Two-hybrid), MS4A1 (Two-hybrid)

ESM2 similar proteins: A8NJ91, A8WTH5, B1WC88, B3M1H7, B3P5J1, B4GPI0, B4HZ81, B4K5X8, B4MBU8, B4NFN4, B4PQ50, B4QZI8, B4R3W7, C1BY38, C3KHG1, O01323, O77286, O97172, P0C8Y2, P0DKX4, Q05B71, Q16EE5, Q28I13, Q29BX8, Q2KI30, Q3ZC78, Q4KMI4, Q56JY4, Q5BL63, Q5F3A1, Q5R4Q3, Q5R7A0, Q6AZM3, Q7PSY2, Q8BU14, Q8LE10, Q8N5K1, Q8TCD1, Q8VCD6, Q91WE4

Diamond homologs: A0A509ADH4, B2RZ37, P0CN16, P0CN17, Q00765, Q07764, Q10010, Q12402, Q29RM3, Q2KI30, Q32LG5, Q3ZCI8, Q4KMI4, Q4P0H0, Q4QQW1, Q4WTW3, Q51VY4, Q5BB01, Q5BL63, Q5HZP8, Q5R598, Q5RE33, Q5XI60, Q60870, Q66IF1, Q682H0, Q6AZM3, Q6BWH8, Q6CE07, Q6CP93, Q6FMU3, Q6NLY8, Q6NUK4, Q6PBX9, Q75A56, Q7ZVX5, Q871R7, Q8BGH4, Q8K072, Q8LE10

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	5	100.2×	1e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	88.4×	1e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	88.4×	1e-07
Activation of BH3-only proteins	5	65.3×	6e-07
RHO GTPases activate PKNs	5	41.7×	4e-06
Intrinsic Pathway for Apoptosis	5	38.5×	6e-06
Apoptosis	6	26.5×	4e-06
Transcriptional and post-translational regulation of MITF-M expression and activity	5	23.5×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	7	13.3×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	63
Likely benign	62
Benign	11

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
864419	NM_001271803.2(REEP2):c.119T>G (p.Met40Arg)	Pathogenic
97002	NM_001271803.2(REEP2):c.107T>A (p.Val36Glu)	Pathogenic
97003	NM_001271803.2(REEP2):c.105+3G>T	Pathogenic
97004	NM_001271803.2(REEP2):c.215T>A (p.Phe72Tyr)	Pathogenic
1029275	NM_001271803.2(REEP2):c.331C>T (p.Arg111Ter)	Likely pathogenic
1029276	NM_001271803.2(REEP2):c.523C>T (p.Arg175Ter)	Likely pathogenic
804453	NM_001271803.2(REEP2):c.696+2T>G	Likely pathogenic

SpliceAI

1067 predictions. Top by Δscore:

Variant	Effect	Δscore
5:138441089:G:GG	donor_gain	1.0000
5:138444412:CA:C	acceptor_loss	1.0000
5:138444413:A:AG	acceptor_gain	1.0000
5:138444413:AG:A	acceptor_gain	1.0000
5:138444414:G:A	acceptor_loss	1.0000
5:138444414:G:GG	acceptor_gain	1.0000
5:138444414:GG:G	acceptor_gain	1.0000
5:138444414:GGTT:G	acceptor_gain	1.0000
5:138444414:GGTTC:G	acceptor_gain	1.0000
5:138444530:G:GT	donor_gain	1.0000
5:138444531:A:T	donor_gain	1.0000
5:138444532:GAAG:G	donor_gain	1.0000
5:138444533:A:T	donor_gain	1.0000
5:138444534:AGGTT:A	donor_loss	1.0000
5:138444535:GG:G	donor_loss	1.0000
5:138444744:A:AG	acceptor_gain	1.0000
5:138444745:A:G	acceptor_gain	1.0000
5:138444752:A:AG	acceptor_gain	1.0000
5:138444753:G:GA	acceptor_loss	1.0000
5:138444753:G:GG	acceptor_gain	1.0000
5:138444864:CAAGG:C	donor_loss	1.0000
5:138444865:AAGG:A	donor_loss	1.0000
5:138444868:G:GA	donor_loss	1.0000
5:138444869:T:G	donor_loss	1.0000
5:138445184:C:A	acceptor_gain	1.0000
5:138445197:C:A	acceptor_gain	1.0000
5:138445198:G:A	acceptor_gain	1.0000
5:138445206:C:A	acceptor_gain	1.0000
5:138445207:G:A	acceptor_gain	1.0000
5:138445211:C:CA	acceptor_gain	1.0000

AlphaMissense

1649 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:138441026:G:C	G15R	1.000
5:138441027:G:A	G15D	1.000
5:138441038:C:T	P19S	1.000
5:138441039:C:A	P19Q	1.000
5:138441042:C:A	A20D	1.000
5:138441044:T:C	Y21H	1.000
5:138441044:T:G	Y21D	1.000
5:138441050:T:C	S23P	1.000
5:138441051:C:T	S23F	1.000
5:138441053:T:G	Y24D	1.000
5:138441058:G:C	K25N	1.000
5:138441058:G:T	K25N	1.000
5:138441059:G:C	A26P	1.000
5:138441060:C:A	A26D	1.000
5:138441391:T:A	W38R	1.000
5:138441391:T:C	W38R	1.000
5:138441403:T:A	W42R	1.000
5:138441403:T:C	W42R	1.000
5:138441405:G:C	W42C	1.000
5:138441405:G:T	W42C	1.000
5:138441416:C:A	A46D	1.000
5:138444439:G:C	K69N	1.000
5:138444439:G:T	K69N	1.000
5:138444444:C:A	A71D	1.000
5:138444453:T:A	I74K	1.000
5:138444455:T:A	W75R	1.000
5:138444455:T:C	W75R	1.000
5:138444459:T:C	L76P	1.000
5:138444462:T:C	L77P	1.000
5:138444479:G:C	G83R	1.000

dbSNP variants (sampled 300 via entrez): RS1000287762 (5:138437319 G>C), RS1000377284 (5:138444606 A>G), RS1000728247 (5:138447393 G>A), RS1000833670 (5:138439340 C>T), RS1000999259 (5:138446137 A>G,T), RS1001162163 (5:138444180 G>A), RS1002395013 (5:138438473 G>A), RS1002542709 (5:138446730 C>T), RS1002896207 (5:138442238 A>G), RS1002907196 (5:138447043 A>T), RS1002914248 (5:138440322 C>G), RS1003254677 (5:138438934 C>A,G), RS1003310174 (5:138439125 TGCCGCC>T,TGCC,TGCCGCCGCC,TGCCGCCGCCGCC,TGCCGCCGCCGCCGCC), RS1004396565 (5:138442154 C>G), RS1004477814 (5:138439865 TG>T)

Disease associations

OMIM: gene MIM:609347 | disease phenotypes: MIM:615625, MIM:270800, MIM:620606

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 72	Strong	Autosomal dominant
hereditary spastic paraplegia	Limited	Autosomal recessive
spastic paraplegia 72b, autosomal recessive	Limited	Autosomal recessive

Mondo (4): hereditary spastic paraplegia 72 (MONDO:0014282), hereditary spastic paraplegia 5A (MONDO:0010047), spastic paraplegia 72b, autosomal recessive (MONDO:0957958), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (2): Autosomal spastic paraplegia type 72 (Orphanet:401849), Autosomal recessive spastic paraplegia type 5A (Orphanet:100986)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001288	Gait disturbance
HP:0001761	Pes cavus
HP:0002063	Rigidity
HP:0002064	Spastic gait
HP:0002066	Gait ataxia
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002174	Postural tremor
HP:0002354	Memory impairment
HP:0002395	Lower limb hyperreflexia
HP:0002839	Urinary bladder sphincter dysfunction
HP:0003487	Babinski sign
HP:0003552	Muscle stiffness
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0006938	Impaired vibration sensation at ankles
HP:0009046	Difficulty running
HP:0011446	Abnormality of mental function
HP:0011463	Childhood onset
HP:0012531	Pain
HP:0030051	Tip-toe gait
HP:0031993	Hoffmann sign

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002539_60	Schizophrenia	5.000000e-09
GCST004521_139	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_66	Autism spectrum disorder or schizophrenia	1.000000e-08
GCST004791_2	Amyotrophic lateral sclerosis (C9orf72 mutation interaction)	2.000000e-06
GCST006990_3	Cerebrospinal AB1-42 levels in Alzheimer’s disease dementia	7.000000e-08
GCST008103_73	Bipolar disorder	8.000000e-07
GCST008115_23	Bipolar I disorder	2.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0009963	bipolar I disorder

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	4
Aflatoxin B1	increases expression, increases methylation	4
Arsenic	decreases expression, increases abundance, affects expression, affects cotreatment	2
aristolochic acid I	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Aldehydes	increases expression	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Mustard Gas	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	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