PRPH

Summary

PRPH (peripherin, HGNC:9461) is a protein-coding gene on chromosome 12q13.12, encoding Peripherin (P41219). Class-III neuronal intermediate filament protein.

This gene encodes a cytoskeletal protein found in neurons of the peripheral nervous system. The encoded protein is a type III intermediate filament protein with homology to other cytoskeletal proteins such as desmin, and is a different protein that the peripherin found in photoreceptors. Mutations in this gene have been associated with susceptibility to amyotrophic lateral sclerosis.

Source: NCBI Gene 5630 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis type 1 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 91 total — 3 likely-pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes
• MANE Select transcript: NM_006262

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9461
Approved symbol	PRPH
Name	peripherin
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	PRPH1
Ensembl gene	ENSG00000135406
Ensembl biotype	protein_coding
OMIM	170710
Entrez	5630

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 retained_intron

ENST00000257860, ENST00000451891, ENST00000530631, ENST00000532332, ENST00000533401, ENST00000537252

RefSeq mRNA: 1 — MANE Select: NM_006262 NM_006262

CCDS: CCDS8783

Canonical transcript exons

ENST00000257860 — 9 exons

Exon	Start	End
ENSE00001279489	49298288	49298686
ENSE00001279494	49295147	49295745
ENSE00003498876	49296178	49296238
ENSE00003501393	49297148	49297273
ENSE00003506308	49297357	49297577
ENSE00003521805	49297677	49297726
ENSE00003529345	49296889	49297056
ENSE00003572461	49296432	49296527
ENSE00003578225	49297958	49298037

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 99.50.

FANTOM5 (CAGE): breadth broad, TPM avg 3.5098 / max 1095.3849, expressed in 271 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125316	3.2967	249
125318	0.0486	4
125315	0.0478	20
125320	0.0410	10
125314	0.0403	16
125321	0.0136	5
125319	0.0130	5
125317	0.0089	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
dorsal root ganglion	UBERON:0000044	99.50	gold quality
trigeminal ganglion	UBERON:0001675	97.43	gold quality
sperm	CL:0000019	96.73	gold quality
male germ cell	CL:0000015	95.78	gold quality
left testis	UBERON:0004533	93.48	gold quality
right testis	UBERON:0004534	93.23	gold quality
testis	UBERON:0000473	91.29	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.58	gold quality
cranial nerve II	UBERON:0000941	88.08	gold quality
sympathetic trunk	UBERON:0000407	86.36	gold quality
right uterine tube	UBERON:0001302	86.15	gold quality
sigmoid colon	UBERON:0001159	85.35	gold quality
transverse colon	UBERON:0001157	82.34	gold quality
colon	UBERON:0001155	81.90	gold quality
large intestine	UBERON:0000059	81.57	gold quality
caecum	UBERON:0001153	81.47	gold quality
mucosa of stomach	UBERON:0001199	81.36	gold quality
type B pancreatic cell	CL:0000169	80.90	gold quality
olfactory bulb	UBERON:0002264	80.80	gold quality
intestine	UBERON:0000160	80.53	gold quality
adult organism	UBERON:0007023	80.48	gold quality
vena cava	UBERON:0004087	80.23	gold quality
vermiform appendix	UBERON:0001154	80.13	gold quality
diaphragm	UBERON:0001103	79.68	gold quality
mucosa of urinary bladder	UBERON:0001259	79.10	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	78.55	gold quality
small intestine	UBERON:0002108	77.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.51	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	4182.72
E-MTAB-11121	yes	1446.01
E-HCAD-10	yes	4.32
E-GEOD-125970	no	3.23
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, TFAP2A

miRNA regulators (miRDB)

24 targeting PRPH, 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-6833-3P	100.00	70.63	3197
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-2355-3P	96.84	68.54	909

Literature-anchored findings (GeneRIF, showing 18)

• The data of this experiment document the expression of peripherin in Lewy body-like inclusions , which may provide a clue to the pathogenesis of neurodegeneration in ALS. (PMID:14675609)
• Peripherin overexpression in transgenic mice can cause defective transport of type IV neurofilament proteins, a phenomenon that may account for the progressive formation of amyotrophic lateral sclerosis-like spheroids in axons. (PMID:16787413)
• peripherin is a novel substrate for Akt in vivo and its phosphorylation may play a role in motor nerve regeneration (PMID:17569669)
• Peripherin splicing abnormalities occur in amyotrophic lateral sclerosis generating aggregation-prone splice isoforms, one of which causes peripherin aggregation when its expression is upregulated. (PMID:18287500)
• PKCepsilon through its interaction with peripherin facilitates its aggregation and subsequent cell death (PMID:18408015)
• Expression of the 2 markers, peripherin and alpha-internexin, in a small round cell tumor strongly favors the diagnosis of neuroblastoma. (PMID:18528283)
• Transgenic mice expressing the PRPH-EGFP genomic reporter display intrinsic peripheral nervous system fluorescence. (PMID:18709437)
• This work contributes to determine the role of PRPH gene variants in ALS. Further studies are necessary to define the mechanisms through which the mutant peripherin could cause ALS phenotype. (PMID:20363051)
• Transgenic peripherin isoform expression reveals post-transcriptional changes to the normal expression pattern associated with malformed filaments and intracellular inclusions underlying a role in the pathogenesis of amyotrophic lateral sclerosis. (PMID:20533992)
• study analyzed expression of peripherin(PP) in the cochlea; in organ of Corti, PP seems to be specifically expressed in outer hair cell afferents; small or type II spiral ganglion cell bodies also intensely express PP (PMID:21088854)
• although the mechanisms underlying peripherin co-localization in Bunina bodies are unknown, peripherin could be involved in forming these inclusions (PMID:21241994)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• interaction between disease-causing RAB7A mutants and peripherin could play an important role in Charcot-Marie-Tooth type 2B neuropathy (PMID:23179371)
• In patients with HD, a panel using calretinin and peripherin with or without MAP-2 may be most helpful in identifying transition zones (PMID:26469323)
• To discover of Phosphorylated autoantigens Peripherin as a Major Humoral Autoantigen in Type 1 Diabetes Mellitus. (PMID:27185639)
• Desmin, Glial Fibrillary Acidic Protein, Vimentin, and Peripherin are type III intermediate filaments that have roles in health and disease [review] (PMID:29196434)
• Mutation in the peripherin gene is associated cone-rod dysfunction or dominant maculopathy. (PMID:30822235)
• Genome-wide association study of sural nerve conduction amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH associated with reduced amplitude of the sural nerve action potential, but not with sural nerve conduction velocity. (PMID:30992453)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	prph	ENSDARG00000028306
mus_musculus	Prph	ENSMUSG00000023484
rattus_norvegicus	Prph	ENSRNOG00000052880

Paralogs (68): KRT33A (ENSG00000006059), VIM (ENSG00000026025), KRT31 (ENSG00000094796), NEFM (ENSG00000104722), KRT23 (ENSG00000108244), KRT37 (ENSG00000108417), KRT32 (ENSG00000108759), KRT18 (ENSG00000111057), LMNB1 (ENSG00000113368), KRT36 (ENSG00000126337), KRT17 (ENSG00000128422), GFAP (ENSG00000131095), KRT34 (ENSG00000131737), KRT33B (ENSG00000131738), NES (ENSG00000132688), KRT85 (ENSG00000135443), KRT7 (ENSG00000135480), KRT71 (ENSG00000139648), INA (ENSG00000148798), LMNTD1 (ENSG00000152936), LMNA (ENSG00000160789), KRT84 (ENSG00000161849), KRT82 (ENSG00000161850), KRT80 (ENSG00000167767), KRT1 (ENSG00000167768), KRT24 (ENSG00000167916), KRT8 (ENSG00000170421), KRT78 (ENSG00000170423), KRT86 (ENSG00000170442), KRT75 (ENSG00000170454), KRT6C (ENSG00000170465), KRT4 (ENSG00000170477), KRT74 (ENSG00000170484), KRT72 (ENSG00000170486), KRT83 (ENSG00000170523), BFSP2 (ENSG00000170819), KRT19 (ENSG00000171345), KRT15 (ENSG00000171346), KRT38 (ENSG00000171360), KRT13 (ENSG00000171401)

Protein

Protein identifiers

Peripherin — P41219 (reviewed: P41219)

Alternative names: Neurofilament 4

All UniProt accessions (3): P41219, F8W835, H7C5W5

UniProt curated annotations — full annotation on UniProt →

Function. Class-III neuronal intermediate filament protein. May form an independent structural network without the involvement of other neurofilaments or may cooperate with the neuronal intermediate filament proteins NEFL, NEFH, NEFM and INA to form a filamentous network. Assembly of the neuronal intermediate filaments may be regulated by RAB7A. Plays a role in the development of unmyelinated sensory neurons. May be involved in axon elongation and axon regeneration after injury. Inhibits neurite extension in type II spiral ganglion neurons in the cochlea.

Subunit / interactions. Forms homodimers (in vitro). Homopolymerizes into a filamentous network (in vitro). Forms heterodimers with NEFL, NEFM or NEFH (in vitro). Interacts with DST (via C-terminus). Interacts with RAB7A; the interaction is direct. Interacts with PRKCE (via phorbol-ester/DAG-type 2 domain).

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Axon. Perikaryon.

Tissue specificity. Expressed in the neurons of the outer hair cells in the organ of Corti and to a lesser extent in type I spiral ganglion cells.

Post-translational modifications. Phosphorylated; phosphorylation increases after nerve injury in regenerating neurons.

Disease relevance. Amyotrophic lateral sclerosis (ALS) [MIM:105400] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Miscellaneous. Gene prediction based on similarity to orthologs.

Similarity. Belongs to the intermediate filament family.

Isoforms (2)

UniProt ID	Names	Canonical?
P41219-1	1	yes
P41219-2	2

RefSeq proteins (1): NP_006253* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002957	Keratin_I	Family
IPR006821	Intermed_filament_DNA-bd	Domain
IPR018039	IF_conserved	Conserved_site
IPR039008	IF_rod_dom	Domain
IPR050405	Intermediate_filament	Family

Pfam: PF00038, PF04732

UniProt features (21 total): region of interest 8, modified residue 6, sequence variant 2, chain 1, domain 1, compositionally biased region 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41219-F1	79.24	0.56

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 (6): 17, 28, 50, 59, 379, 470

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 223 (showing top): MORF_RAGE, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, LUCAS_HNF4A_TARGETS_UP, GGGTGGRR_PAX4_03, CAR_MYST2, SCHAEFFER_PROSTATE_DEVELOPMENT_12HR_DN, SCHLOSSER_SERUM_RESPONSE_DN, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, CAR_MLANA, MORF_PML, GOCC_NEURON_PROJECTION, MORF_PDPK1, MORF_IKBKG, CTGYNNCTYTAA_UNKNOWN

GO Biological Process (1): intermediate filament organization (GO:0045109)

GO Molecular Function (3): structural molecule activity (GO:0005198), structural constituent of cytoskeleton (GO:0005200), protein binding (GO:0005515)

GO Cellular Component (11): intermediate filament (GO:0005882), plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), perikaryon (GO:0043204), type III intermediate filament (GO:0045098), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995), intermediate filament cytoskeleton (GO:0045111)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoskeleton	2
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
molecular_function	1
structural molecule activity	1
cytoskeleton organization	1
binding	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1
membrane	1
cell periphery	1
neuron projection	1
neuronal cell body	1
intermediate filament	1
extracellular vesicle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

266 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRPH	TPST2	O60704	306
PRPH	PDE6G	P18545	276
PRPH	KRTDAP	P60985	266
PRPH	PRPH2	P23942	261
PRPH	RHPN2	Q8IUC4	254
PRPH	PARP16	Q8N5Y8	254
PRPH	LYPLA2	O95372	250
PRPH	PARP4	Q9UKK3	250
PRPH	SBSN	Q6UWP8	249
PRPH	DPF1	Q92782	238
PRPH	SSTR2	P30874	223
PRPH	UBAC1	Q9BSL1	222
PRPH	SPG11	Q96JI7	220
PRPH	EGR3	Q06889	214
PRPH	TIPARP	Q7Z3E1	207

IntAct

295 interactions, top by confidence:

A	B	Type	Score
DES	PRPH	psi-mi:“MI:0915”(physical association)	0.780
KRT20	PRPH	psi-mi:“MI:0915”(physical association)	0.720
PRPH	LNX1	psi-mi:“MI:0915”(physical association)	0.720
KRT19	PRPH	psi-mi:“MI:0915”(physical association)	0.720
PRPH	TCP10L	psi-mi:“MI:0915”(physical association)	0.720
LNX1	PRPH	psi-mi:“MI:0915”(physical association)	0.720
TCP10L	PRPH	psi-mi:“MI:0915”(physical association)	0.720
VIM	PRPH	psi-mi:“MI:0915”(physical association)	0.670
FAM167A	PRPH	psi-mi:“MI:0915”(physical association)	0.670
PRPH	ZC4H2	psi-mi:“MI:0915”(physical association)	0.560
KRT16	PRPH	psi-mi:“MI:0915”(physical association)	0.560
PRPH	NXF1	psi-mi:“MI:0915”(physical association)	0.560
DDX6	PRPH	psi-mi:“MI:0915”(physical association)	0.560
PRPH	ZNF572	psi-mi:“MI:0915”(physical association)	0.560
PRPH	MAGOHB	psi-mi:“MI:0915”(physical association)	0.560
PRPH	PRKAA2	psi-mi:“MI:0915”(physical association)	0.560
PRPH	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
PRPH	PPP1R13B	psi-mi:“MI:0915”(physical association)	0.560
PSMA1	PRPH	psi-mi:“MI:0915”(physical association)	0.560
PRPH	CDC37	psi-mi:“MI:0915”(physical association)	0.560
KRT75	PRPH	psi-mi:“MI:0915”(physical association)	0.560
PRPH	LENG1	psi-mi:“MI:0915”(physical association)	0.560
PRPH	TTC23	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (223): PRPH (Two-hybrid), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-Western), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Affinity Capture-MS), PRPH (Proximity Label-MS)

ESM2 similar proteins: A0JND2, A3KN27, A6BLY7, A6H712, A6QNX5, A6QQJ3, A7YWK3, D3ZER2, E1AB55, O76014, O76015, P08552, P15331, P21807, P35617, P41219, P46660, P48670, Q0VBK2, Q13515, Q148H5, Q148H6, Q148H8, Q14CN4, Q28177, Q3SY84, Q3TRJ4, Q6A162, Q6IFW3, Q6IFW8, Q6IFX0, Q6IFX4, Q6IFZ9, Q6IG04, Q6IME9, Q6IMF1, Q6KB66, Q6NVD9, Q6NXH9, Q7RTS7

Diamond homologs: A0A8C0N8E3, A5A6M8, A5A6N0, A6QQJ3, B4F721, O62654, O77788, O93532, O95678, P02538, P02540, P02541, P02542, P02543, P02544, P02547, P02548, P03995, P04259, P05786, P05787, P07196, P07197, P08551, P08552, P08553, P08670, P08729, P08776, P09654, P11679, P12035, P12036, P12839, P13647, P14136, P15331, P16053, P16878, P16884

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AKT	“up-regulates activity”	PRPH	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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
Formation of the cornified envelope	9	13.9×	6e-06
Keratinization	9	8.8×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	8	32.8×	3e-08
intermediate filament organization	11	31.5×	2e-11
epithelial cell differentiation	8	16.7×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	64
Likely benign	3
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1333542	NM_006262.4(PRPH):c.607-1G>A	Likely pathogenic
3234975	NM_006262.4(PRPH):c.919C>T (p.Gln307Ter)	Likely pathogenic
4845223	NM_006262.4(PRPH):c.745C>T (p.Gln249Ter)	Likely pathogenic

SpliceAI

1192 predictions. Top by Δscore:

Variant	Effect	Δscore
12:49296172:C:CA	acceptor_gain	1.0000
12:49296175:CAG:C	acceptor_loss	1.0000
12:49296177:G:GT	acceptor_loss	1.0000
12:49296234:GCAAG:G	donor_gain	1.0000
12:49296237:AG:A	donor_gain	1.0000
12:49296237:AGGT:A	donor_loss	1.0000
12:49296238:GG:G	donor_gain	1.0000
12:49296238:GGTG:G	donor_loss	1.0000
12:49296239:G:C	donor_loss	1.0000
12:49296239:G:GG	donor_gain	1.0000
12:49296240:T:A	donor_loss	1.0000
12:49296415:A:AG	acceptor_gain	1.0000
12:49296415:ACT:A	acceptor_gain	1.0000
12:49296417:T:TA	acceptor_gain	1.0000
12:49296421:A:AG	acceptor_gain	1.0000
12:49296427:C:CA	acceptor_gain	1.0000
12:49296523:AGGAG:A	donor_gain	1.0000
12:49296524:GGAG:G	donor_gain	1.0000
12:49296524:GGAGG:G	donor_gain	1.0000
12:49296525:G:GT	donor_gain	1.0000
12:49296525:GAG:G	donor_gain	1.0000
12:49296526:AG:A	donor_gain	1.0000
12:49296527:GG:G	donor_gain	1.0000
12:49296528:G:GG	donor_gain	1.0000
12:49296820:T:A	acceptor_gain	1.0000
12:49296822:T:TA	acceptor_gain	1.0000
12:49296825:A:AG	acceptor_gain	1.0000
12:49296825:AC:A	acceptor_gain	1.0000
12:49296826:C:CA	acceptor_gain	1.0000
12:49296831:T:A	acceptor_gain	1.0000

AlphaMissense

3041 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:49295502:T:C	L101P	1.000
12:49295511:T:C	L104P	1.000
12:49295520:G:C	R107P	1.000
12:49295523:T:C	F108S	1.000
12:49296444:G:C	A207P	1.000
12:49297505:T:C	L382P	1.000
12:49297508:T:C	L383P	1.000
12:49297518:G:C	K386N	1.000
12:49297518:G:T	K386N	1.000
12:49297526:T:A	L389Q	1.000
12:49297526:T:C	L389P	1.000
12:49297536:G:C	E392D	1.000
12:49297536:G:T	E392D	1.000
12:49297538:T:A	I393N	1.000
12:49297538:T:G	I393S	1.000
12:49297540:G:C	A394P	1.000
12:49297550:G:C	R397P	1.000
12:49297556:T:C	L399P	1.000
12:49295511:T:A	L104H	0.999
12:49295513:A:G	N105D	0.999
12:49295514:A:T	N105I	0.999
12:49295515:C:A	N105K	0.999
12:49295515:C:G	N105K	0.999
12:49295535:T:A	I112N	0.999
12:49295553:T:C	L118P	0.999
12:49296457:G:C	R211P	0.999
12:49296466:T:C	L214P	0.999
12:49296487:T:C	L221P	0.999
12:49296504:T:C	F227L	0.999
12:49296506:C:A	F227L	0.999

dbSNP variants (sampled 300 via entrez): RS1000240032 (12:49293212 C>T), RS1000850642 (12:49294419 C>A), RS1001473683 (12:49298647 G>T), RS1001857400 (12:49298136 T>A,G), RS1001899606 (12:49293166 C>A,G,T), RS1002905908 (12:49294179 A>G), RS1003357571 (12:49293973 T>C), RS1004438127 (12:49299162 G>A,T), RS1004964552 (12:49293709 C>T), RS1005384124 (12:49293927 C>G), RS1006380669 (12:49295072 G>A,C), RS1006935556 (12:49296725 C>G,T), RS1007991466 (12:49298745 C>T), RS1008804199 (12:49293251 T>A), RS1008823881 (12:49293434 C>G,T)

Disease associations

OMIM: gene MIM:170710 | disease phenotypes: MIM:105400

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 1	Moderate	Autosomal dominant
amyotrophic lateral sclerosis	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Limited	AD

Mondo (2): amyotrophic lateral sclerosis type 1 (MONDO:0007103), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (1): Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002314	Degeneration of the lateral corticospinal tracts
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002398	Degeneration of anterior horn cells
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001148_9	Prostate cancer	7.000000e-12
GCST008312_1	Sural nerve amplitude potential	1.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010070	nerve conduction amplitude

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
C531617	Amyotrophic lateral sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066904 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.39	Kd	40.97	nM	CHEMBL3752910
6.75	ED50	178.3	nM	CHEMBL3752910
6.40	Kd	399.6	nM	CHEMBL5653589
5.76	ED50	1739	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149094: Binding affinity to human PRPH incubated for 45 mins by Kinobead based pull down assay	kd	0.0410	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149094: Binding affinity to human PRPH incubated for 45 mins by Kinobead based pull down assay	kd	0.3996	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
arsenite	increases methylation	1
sulforaphane	affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
ferrous chloride	decreases expression	1
pentanal	increases expression	1
monomethylarsonous acid	increases expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Aldehydes	increases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	increases expression	1
Caffeine	decreases expression	1
Cannabidiol	increases expression	1
Cisplatin	affects expression	1
Copper	affects binding, increases expression	1
Cytarabine	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Dimethyl Sulfoxide	affects expression	1
Ivermectin	decreases expression	1
Silicon Dioxide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652136	Binding	Binding affinity to human PRPH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS