REEP1

Summary

REEP1 (receptor accessory protein 1, HGNC:25786) is a protein-coding gene on chromosome 2p11.2, encoding Receptor expression-enhancing protein 1 (Q9H902). Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton.

This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 65055 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 31 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 477 total — 62 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 75
• MANE Select transcript: NM_001371279

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25786
Approved symbol	REEP1
Name	receptor accessory protein 1
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13110, SPG31, Yip2a
Ensembl gene	ENSG00000068615
Ensembl biotype	protein_coding
OMIM	609139
Entrez	65055

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 18 protein_coding, 5 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000165698, ENST00000453231, ENST00000473407, ENST00000475475, ENST00000489855, ENST00000490915, ENST00000535845, ENST00000538924, ENST00000541910, ENST00000642243, ENST00000643817, ENST00000644644, ENST00000646181, ENST00000686220, ENST00000687696, ENST00000687927, ENST00000688400, ENST00000689156, ENST00000691093, ENST00000691703, ENST00000692664, ENST00000693329, ENST00000908467, ENST00000908468, ENST00000943694

RefSeq mRNA: 8 — MANE Select: NM_001371279 NM_001164730, NM_001164731, NM_001164732, NM_001371279, NM_001371280, NM_001410855, NM_001410856, NM_022912

CCDS: CCDS1989, CCDS54372, CCDS54373, CCDS54374, CCDS92795, CCDS92796, CCDS92797, CCDS92798

Canonical transcript exons

ENST00000538924 — 9 exons

Exon	Start	End
ENSE00003474551	86337479	86337626
ENSE00003480969	86282170	86282242
ENSE00003537521	86213993	86217110
ENSE00003582926	86232625	86232802
ENSE00003606640	86251957	86252070
ENSE00003698407	86263965	86264041
ENSE00003700390	86254694	86254814
ENSE00003792365	86219970	86220121
ENSE00003798694	86227363	86227398

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.39.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7501 / max 183.6549, expressed in 554 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29541	1.9673	477
29540	1.3017	341
29539	0.4810	185

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
dorsal root ganglion	UBERON:0000044	99.39	gold quality
middle temporal gyrus	UBERON:0002771	98.59	gold quality
cortical plate	UBERON:0005343	98.51	gold quality
substantia nigra pars compacta	UBERON:0001965	98.46	gold quality
cauda epididymis	UBERON:0004360	98.41	gold quality
pons	UBERON:0000988	98.30	gold quality
superior vestibular nucleus	UBERON:0007227	98.15	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.06	gold quality
orbitofrontal cortex	UBERON:0004167	98.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.76	gold quality
germinal epithelium of ovary	UBERON:0001304	97.60	gold quality
adult organism	UBERON:0007023	97.46	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.43	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.42	gold quality
biceps brachii	UBERON:0001507	96.92	gold quality
postcentral gyrus	UBERON:0002581	96.83	gold quality
entorhinal cortex	UBERON:0002728	96.74	gold quality
parietal lobe	UBERON:0001872	96.73	gold quality
superior frontal gyrus	UBERON:0002661	96.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.57	gold quality
trigeminal ganglion	UBERON:0001675	96.30	gold quality
diaphragm	UBERON:0001103	95.71	gold quality
saphenous vein	UBERON:0007318	95.70	gold quality
blood vessel layer	UBERON:0004797	95.44	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.06	gold quality
ganglionic eminence	UBERON:0004023	95.02	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.72	gold quality
myocardium	UBERON:0002349	94.71	gold quality
medulla oblongata	UBERON:0001896	94.62	gold quality
triceps brachii	UBERON:0001509	94.52	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	340.10
E-GEOD-93593	yes	20.81
E-CURD-10	no	70.83
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

194 targeting REEP1, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382

Literature-anchored findings (GeneRIF, showing 23)

• RTP and REEP gene expression in human circumvallate papillae and testis, both of which are sites of taste receptor gene expression. (PMID:16720576)
• REEP1 is widely expressed and localizes to mitochondria, which underlines the importance of mitochondrial function in neurodegenerative disease. (PMID:16826527)
• Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia type SPG31. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients. (PMID:18321925)
• Our results confirm the previously observed mutation range of 3% to 6.5%, respectively, and they widen the spectrum of REEP1 mutations (PMID:18644145)
• Results identify the frequency of REEP1 mutations in both autosomal dominant HSP (ADHSP) and sporadic spastic paraparesis (SSP) and analyse the genotype/phenotype correlation of mutations so far described in REEP1. (PMID:19034539)
• A novel splice-site mutation (REEP1 c417+1g>a) was identified in chiease family of ADHSP. (PMID:19072839)
• Receptor expression-enhancing protein 1 gene (SPG31) mutations are rare in Chinese Han patients with hereditary spastic paraplegia. (PMID:19781397)
• Hereditary spastic paraplegias(HSP) proteins atlastin-1, spastin, and REEP1 interact within the tubularER membrane in corticospinal neurons to coordinate ER shaping and microtubule dynamics. (PMID:20200447)
• previously unreported autosomal dominant mutations in the REEP1 gene in hereditary spastic paraplegia (PMID:20718791)
• Identification of 12 different heterozygous REEP1 mutations, including two exon deletions, associated with either a pure or a complex phenotype. (PMID:21618648)
• Whole-exome sequencing of two affected individuals revealed a single candidate variant within the linking regions, i.e., a splice-site alteration in REEP1 (PMID:22703882)
• A novel REEP1 mutation is identified in a cohort of patients with upper motor neuron syndrome. (PMID:23108492)
• REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the endoplasmic reticulum. (PMID:24051375)
• 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)
• Functional mutation analysis reveal that distinct pathomechanisms are associated with REEP1 mutations and shed new light on its probable functions. (PMID:24478229)
• Nonsense variants in REEP1 causing haploinsufficiency/loss of function are responsible for autosomal dominant hereditary spastic paraplegia (HSP)-type SPG31. (PMID:24986827)
• we show that REEP1 facilitates endoplasmic reticulum mitochondria interactions, a function diminished by disease-associated mutations. (PMID:26201691)
• This study demonstrated that REEP1 gene mutation associated with hereditary spastic paraplegias in group of Polish patients (PMID:26671083)
• Pathology of spastic paraplegia type 31 may contain dosage effect of REEP1 transcripts. (PMID:29107646)
• Study identified a heterozygous nonstop variant in REEP1. Mutations in this gene have classically been associated with the upper motor neuron disorder hereditary spastic paraplegia (HSP). (PMID:29124833)
• The REEP1 c.606 + 43G>T caused Spastic Paraplegia and primary progressive multiple sclerosis. (PMID:29908077)
• REEP1 variants cause polyneuropathy in SPG31. (PMID:30637453)
• deletional variation of the REEP1 gene probably underlies the disease in this pedigree (PMID:31055810)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	reep1	ENSDARG00000014854
mus_musculus	Reep1	ENSMUSG00000052852
rattus_norvegicus	Reep1	ENSRNOG00000008481
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): REEP6 (ENSG00000115255), REEP5 (ENSG00000129625), REEP2 (ENSG00000132563), REEP3 (ENSG00000165476), REEP4 (ENSG00000168476)

Protein

Protein identifiers

Receptor expression-enhancing protein 1 — Q9H902 (reviewed: Q9H902)

Alternative names: Spastic paraplegia 31 protein

All UniProt accessions (13): Q9H902, A0A1C7CYY3, A0A2R8Y5P1, A0A2R8Y6K6, A0A2R8YD64, A0A8I5KQB8, A0A8I5KQI3, A0A8I5KRE1, A0A8I5KTB5, A0A8I5KTX0, A0A8I5KX93, A0A8I5QKJ2, U3KPV7

UniProt curated annotations — full annotation on UniProt →

Function. Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton. May also enhance the cell surface expression of odorant receptors. May play a role in long-term axonal maintenance.

Subunit / interactions. Interacts with SPAST and ATL1; it preferentially interacts with SPAST isoform 1. Interacts (via C-terminus) with microtubules. Interacts with odorant receptor proteins. Interacts with ZFYVE27.

Subcellular location. Membrane. Mitochondrion membrane. Endoplasmic reticulum.

Tissue specificity. Expressed in circumvallate papillae and testis.

Disease relevance. Spastic paraplegia 31, autosomal dominant (SPG31) [MIM:610250] 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 dominant 12 (HMND12) [MIM:614751] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMND12 is characterized by onset in the first or second decade of distal muscle weakness and atrophy, primarily affecting the intrinsic hand muscles, but also affecting the lower legs, resulting in abnormal gait and pes cavus. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, autosomal recessive 6 (HMNR6) [MIM:620011] A form of distal spinal muscular atrophy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMNR6 is characterized by onset of distal muscle weakness in early infancy. Affected individuals often present at birth with distal joint contractures or foot deformities and show delayed motor development, often with inability to walk or frequent falls. Patients often show respiratory distress or diaphragmatic palsy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DP1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9H902-1	1	yes
Q9H902-2	2
Q9H902-3	3
Q9H902-4	4

RefSeq proteins (8): NP_001158202, NP_001158203, NP_001158204, NP_001358208, NP_001358209, NP_001397784, NP_001397785, NP_075063 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004345	TB2_DP1_HVA22	Family

Pfam: PF03134

UniProt features (17 total): sequence variant 8, splice variant 3, transmembrane region 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H902-F1	67.91	0.04

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): 152

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9752946	Expression and translocation of olfactory receptors

MSigDB gene sets: 385 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, BENPORATH_ES_WITH_H3K27ME3, MCLACHLAN_DENTAL_CARIES_UP, FISCHER_G1_S_CELL_CYCLE, PEREZ_TP63_TARGETS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, CAGCTG_AP4_Q5, AGTCTTA_MIR499, ONKEN_UVEAL_MELANOMA_UP, AAACCAC_MIR140, LE_EGR2_TARGETS_UP, BILD_E2F3_ONCOGENIC_SIGNATURE, MODULE_206, TGTGTGA_MIR377

GO Biological Process (2): protein insertion into membrane (GO:0051205), endoplasmic reticulum tubular network organization (GO:0071786)

GO Molecular Function (3): microtubule binding (GO:0008017), olfactory receptor binding (GO:0031849), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytoplasmic microtubule (GO:0005881), membrane (GO:0016020), mitochondrial membrane (GO:0031966), endoplasmic reticulum tubular network (GO:0071782), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Olfactory Signaling Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
organelle membrane	2
endoplasmic reticulum subcompartment	2
intracellular protein localization	1
membrane organization	1
establishment of protein localization to membrane	1
endoplasmic reticulum organization	1
tubulin binding	1
G protein-coupled receptor binding	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
microtubule	1
mitochondrion	1
mitochondrial envelope	1

Protein interactions and networks

STRING

1200 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
REEP1	ATL1	Q8WXF7	982
REEP1	SPAST	Q9UBP0	976
REEP1	RTP2	Q5QGT7	976
REEP1	RTP1	P59025	959
REEP1	ATL3	Q6DD88	950
REEP1	ATL2	Q8NHH9	949
REEP1	WASHC5	Q12768	917
REEP1	ZFYVE27	Q5T4F4	915
REEP1	NIPA1	Q7RTP0	901
REEP1	KIF5A	Q12840	842
REEP1	RTN2	O75298	750
REEP1	BSCL2	Q96G97	744
REEP1	SPG11	Q96JI7	741
REEP1	SPG7	Q9UQ90	691
REEP1	ALDH18A1	P54886	663

IntAct

47 interactions, top by confidence:

A	B	Type	Score
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
STX7	REEP1	psi-mi:“MI:0915”(physical association)	0.560
REEP1	TMEM100	psi-mi:“MI:0915”(physical association)	0.560
CSRP1	REEP1	psi-mi:“MI:0915”(physical association)	0.560
TMEM42	REEP1	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	REEP1	psi-mi:“MI:0915”(physical association)	0.560
CLDN10	REEP1	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	REEP1	psi-mi:“MI:0915”(physical association)	0.560
KCNA10	GAPDHS	psi-mi:“MI:0914”(association)	0.530
REEP1	PLSCR1	psi-mi:“MI:0914”(association)	0.530
ZFYVE27	REEP1	psi-mi:“MI:0915”(physical association)	0.400
CAV3	SHTN1	psi-mi:“MI:0914”(association)	0.350
LYPD3	CLASP2	psi-mi:“MI:0914”(association)	0.350
CUL4B	GGTLC3	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
LYPD3	TNPO2	psi-mi:“MI:0914”(association)	0.350
REEP3	RAB3GAP1	psi-mi:“MI:0914”(association)	0.350
REEP5	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAPT	PITPNM1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (48): REEP1 (Affinity Capture-MS), PLSCR1 (Affinity Capture-MS), REEP1 (Affinity Capture-MS), REEP1 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), NCAM1 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), REEP2 (Affinity Capture-MS), YWHAG (Affinity Capture-MS), REEP1 (Affinity Capture-MS), REEP1 (Affinity Capture-MS), REEP1 (Affinity Capture-Western), REEP1 (Affinity Capture-Western), REEP1 (Affinity Capture-MS), STX7 (Two-hybrid)

ESM2 similar proteins: A4R0J5, B8JLV7, F4I8Q7, F4JTN2, O14828, O24060, O35609, O64614, O75915, O80915, P53633, Q08D83, Q28D16, Q3UDR8, Q4R4R4, Q56P28, Q58DR5, Q5E9M1, Q5F433, Q5J6M8, Q5R4X8, Q5RBL9, Q5XF36, Q68EW1, Q6TUD4, Q6ZQE4, Q7S158, Q8BGH4, Q8LFP1, Q8R5J9, Q93VH1, Q95MN4, Q9C889, Q9ERN0, Q9ES40, Q9FLB6, Q9FY84, Q9GZM5, Q9H902, Q9JIG8

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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	31
Uncertain significance	192
Likely benign	101
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012952	NM_001371279.1(REEP1):c.175del (p.Leu59fs)	Pathogenic
1069793	NM_001371279.1(REEP1):c.417+1G>C	Pathogenic
1071529	NC_000002.11:g.(?86444152)(86564643_?)del	Pathogenic
1073769	NM_001371279.1(REEP1):c.417+1G>A	Pathogenic
1073869	NM_001371279.1(REEP1):c.224G>A (p.Trp75Ter)	Pathogenic
1076331	NM_001371279.1(REEP1):c.345C>G (p.Tyr115Ter)	Pathogenic
1184968	NM_001371279.1(REEP1):c.72del (p.Ser23_Tyr24insTer)	Pathogenic
1256311	NM_001371279.1(REEP1):c.450dup (p.Phe151fs)	Pathogenic
1299770	NM_001371279.1(REEP1):c.417+1G>T	Pathogenic
1299771	NM_001371279.1(REEP1):c.301A>T (p.Lys101Ter)	Pathogenic
1343954	NM_001371279.1(REEP1):c.344dup (p.Tyr115Ter)	Pathogenic
1452761	NM_001371279.1(REEP1):c.460C>T (p.Gln154Ter)	Pathogenic
1459865	NC_000002.11:g.(?86509273)(86564633_?)del	Pathogenic
1694461	NM_001164730.2(REEP1):c.40dup (p.Arg14fs)	Pathogenic
1703490	NM_022912.2(REEP1):c.106delG	Pathogenic
1703514	NM_001371279.1(REEP1):c.124T>C (p.Trp42Arg)	Pathogenic
1859	NM_001371279.1(REEP1):c.512del (p.Pro171fs)	Pathogenic
1860	NM_001371279.1(REEP1):c.183-2A>G	Pathogenic
1863	NM_001371279.1(REEP1):c.337C>T (p.Arg113Ter)	Pathogenic
188118	NM_001371279.1(REEP1):c.415A>T (p.Lys139Ter)	Pathogenic
1996533	NM_001371279.1(REEP1):c.57del (p.Ala20fs)	Pathogenic
2036306	NM_001371279.1(REEP1):c.304-1G>C	Pathogenic
2100758	NM_001371279.1(REEP1):c.417+1del	Pathogenic
2118484	NM_001371279.1(REEP1):c.128_138dup (p.Phe48fs)	Pathogenic
217864	NM_001371279.1(REEP1):c.303+1_303+7delinsAC	Pathogenic
224884	NM_001371279.1(REEP1):c.595+1G>A	Pathogenic
2426782	NC_000002.11:g.(?86479060)(86481957_?)del	Pathogenic
253380	GRCh37/hg19 2p11.2(chr2:86441169-86509452)x3	Pathogenic
2571080	NM_001371279.1(REEP1):c.304-2A>C	Pathogenic
2616434	NM_001371279.1(REEP1):c.327del (p.Ala110fs)	Pathogenic

SpliceAI

2685 predictions. Top by Δscore:

Variant	Effect	Δscore
2:86251869:AG:A	donor_gain	1.0000
2:86251944:T:TA	donor_gain	1.0000
2:86251951:CAGTA:C	donor_loss	1.0000
2:86251952:AGTAC:A	donor_loss	1.0000
2:86251953:GTA:G	donor_loss	1.0000
2:86251954:TA:T	donor_loss	1.0000
2:86251955:A:T	donor_loss	1.0000
2:86251956:C:A	donor_loss	1.0000
2:86252066:ATTTC:A	acceptor_gain	1.0000
2:86252067:TTTC:T	acceptor_gain	1.0000
2:86252068:TTC:T	acceptor_gain	1.0000
2:86252069:TC:T	acceptor_gain	1.0000
2:86252070:CC:C	acceptor_gain	1.0000
2:86252070:CCT:C	acceptor_loss	1.0000
2:86252071:C:CC	acceptor_gain	1.0000
2:86252071:CTGT:C	acceptor_loss	1.0000
2:86252075:C:CT	acceptor_gain	1.0000
2:86254688:TATTA:T	donor_loss	1.0000
2:86254689:ATTAC:A	donor_loss	1.0000
2:86254690:TTAC:T	donor_loss	1.0000
2:86254691:TA:T	donor_loss	1.0000
2:86254692:A:C	donor_loss	1.0000
2:86254693:C:CA	donor_loss	1.0000
2:86254729:T:TA	donor_gain	1.0000
2:86254815:C:CC	acceptor_gain	1.0000
2:86254815:CTGG:C	acceptor_loss	1.0000
2:86254816:T:A	acceptor_loss	1.0000
2:86263959:ACTT:A	donor_loss	1.0000
2:86263960:CTT:C	donor_loss	1.0000
2:86263961:TTA:T	donor_loss	1.0000

AlphaMissense

1847 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:86251964:G:T	A137D	1.000
2:86251968:C:G	A136P	1.000
2:86251976:G:T	A133D	1.000
2:86251977:C:G	A133P	1.000
2:86251980:C:G	A132P	1.000
2:86251985:G:T	A130D	1.000
2:86251986:C:G	A130P	1.000
2:86251988:G:T	A129D	1.000
2:86252009:C:T	G122E	1.000
2:86252046:C:G	A110P	1.000
2:86254710:A:G	L96P	1.000
2:86254710:A:T	L96Q	1.000
2:86254735:A:C	Y88D	1.000
2:86254749:C:T	G83D	1.000
2:86254750:C:A	G83C	1.000
2:86254750:C:G	G83R	1.000
2:86254770:A:G	L76P	1.000
2:86254774:A:G	W75R	1.000
2:86254774:A:T	W75R	1.000
2:86254785:G:T	A71E	1.000
2:86254790:T:A	K69N	1.000
2:86254790:T:G	K69N	1.000
2:86264010:G:T	A46E	1.000
2:86264016:A:T	I44K	1.000
2:86264021:C:A	W42C	1.000
2:86264021:C:G	W42C	1.000
2:86264023:A:G	W42R	1.000
2:86264023:A:T	W42R	1.000
2:86264035:A:G	W38R	1.000
2:86264035:A:T	W38R	1.000

dbSNP variants (sampled 300 via entrez): RS1000010099 (2:86227481 G>C), RS1000024017 (2:86269783 A>G), RS1000027653 (2:86323811 C>A,T), RS1000051604 (2:86269956 A>G), RS1000101319 (2:86313565 G>T), RS1000108692 (2:86220335 G>C), RS1000139804 (2:86219925 CTT>C), RS1000184628 (2:86224843 A>C), RS1000219655 (2:86333165 C>A,T), RS1000247111 (2:86244219 A>G), RS1000283290 (2:86290941 C>T), RS1000307328 (2:86310489 T>C), RS1000370968 (2:86213580 C>T), RS1000371588 (2:86277881 T>G), RS1000373536 (2:86240994 G>A,C)

Disease associations

OMIM: gene MIM:609139 | disease phenotypes: MIM:610250, MIM:614751, MIM:303350, MIM:620011, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 31	Definitive	Autosomal dominant
neuronopathy, distal hereditary motor, type 5B	Strong	Autosomal dominant
spinal muscular atrophy, distal, autosomal recessive, 6	Strong	Autosomal recessive
neuronopathy, distal hereditary motor, type 5A	Supportive	Autosomal dominant

Mondo (7): hereditary spastic paraplegia 31 (MONDO:0012453), neuronopathy, distal hereditary motor, type 5B (MONDO:0013884), hereditary spastic paraplegia (MONDO:0019064), spinal muscular atrophy, distal, autosomal recessive, 6 (MONDO:0859279), Charcot-Marie-Tooth disease (MONDO:0015626), polyneuropathy (MONDO:0001824), neuronopathy, distal hereditary motor, type 5A (MONDO:0015353)

Orphanet (4): Autosomal dominant spastic paraplegia type 31 (Orphanet:101011), Distal hereditary motor neuropathy type 5 (Orphanet:139536), Hereditary spastic paraplegia (Orphanet:685), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000218	High palate
HP:0001252	Hypotonia
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001276	Hypertonia
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001765	Hammertoe
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002098	Respiratory distress
HP:0002317	Unsteady gait
HP:0002359	Frequent falls
HP:0002376	Developmental regression
HP:0002395	Lower limb hyperreflexia
HP:0002460	Distal muscle weakness
HP:0002483	Bulbar signs
HP:0002495	Impaired vibratory sensation
HP:0002936	Distal sensory impairment
HP:0003202	Skeletal muscle atrophy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003542_125	Night sleep phenotypes	5.000000e-06
GCST004730_1	Facial emotion recognition (sad faces)	2.000000e-06
GCST006061_54	Atrial fibrillation	3.000000e-10
GCST006061_55	Atrial fibrillation	4.000000e-11
GCST006414_67	Atrial fibrillation	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008329	facial emotion recognition measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D011115	Polyneuropathies	C10.668.829.800
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
C565210	Spastic Paraplegia 31, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression, affects expression	9
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Aflatoxin B1	increases methylation, affects expression, decreases expression	3
Benzo(a)pyrene	affects methylation	2
Cadmium	decreases expression, increases abundance, increases expression	2
Estradiol	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Nickel	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
sotorasib	affects cotreatment, increases expression	1
methyleugenol	decreases expression	1
uranyl acetate	affects expression	1
bisphenol A	increases methylation	1
methylselenic acid	increases expression	1
trichostatin A	increases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
pentanal	increases expression	1
dinophysistoxin 1	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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Doxorubicin	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D5H9	HIHCNi008-A-3	Induced pluripotent stem cell	Male
CVCL_D5HA	HIHCNi008-A-4	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
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