PDYN

protein-coding

prodynorphin, the group of Neuropeptides

Gene summary

The protein encoded by this gene is a preproprotein that is proteolytically processed to form the secreted opioid peptides beta-neoendorphin, dynorphin, leu-enkephalin, rimorphin, and leumorphin. These peptides are ligands for the kappa-type of opioid receptor. Dynorphin is involved in modulating responses to several psychoactive substances, including cocaine. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]

Previous symbols:

SCA23

MANE transcript

NM_024411.5

Inheritance

ClinVar variants

P:2U:108B:50

Top phenotype

Spinocerebellar ataxia 23

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr20:1,978,757-1,994,285

External References & Databases

Ensembl (ENSG00000101327)

Transcript & Mutation Effects

hg38 • Region Span ~15.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 23LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012449

Submitter: ClinGen

*PDYN* was first reported in relation to autosomal dominant spinocerebellar ataxia in 2004 (Verbeck et al., PMID: 15306549). Evidence supporting this gene-disease relationship includes case-level data and experimental data. *PDYN* variants were reported in as low as 0.1% of ataxia cohorts (PMIDs: 15306549, 21035104, 22287014, 23108490, 23471613, 25595316, 32587707). For the purposes of this gene disease validity curation, the ClinGen Cerebellar Ataxia Gene Curation Expert Panel estimates the expected frequency of *PDYN* variants in ataxia to be less than 1 in 100,000 (0.00001) based on the available literature on *PDYN* as well as prevalence studies in undiagnosed ataxia cohorts (PMIDs: 25133958, 25497598, 29482223, 29915382, 31692161, 34234304). Twelve variants reported in fourteen probands with autosomal dominant spinocerebellar ataxia are included in this curation, however, most of them had minor allele frequencies above this threshold (PMIDs: 21035104, 22287014, 22985506, 23108490, 23471613, 27190015, 29915382, 32587707, 42008026). Therefore, evidentiary values of the variants in this curation were adjusted accordingly. For example, the recurrent variant *PDYN*:p.R138S has been reported in three unrelated probands (PMIDs: 21035104, 22287014, 42008026), was shown to segregate with disease in nine additional family members of a large Dutch pedigree (PMID: 15306549) and exhibited reduced dynorphin B and Leu-enkephalin processing via *in vitro* functional assay (PMID: 21035104). However, this variant’s evidentiary score was reduced as its minor allele frequency is above 0.00001 with observations in 84 of 1614078 alleles in gnomADv4. This gene-disease relationship is supported by expression studies, a mouse model and *in vitro* functional assays. Bulk tissue gene expression data from the GTEx Portal indicates *PDYN* is highly expressed in the brain but with very low expression in the cerebellum (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Transgenic mice with the *PDYN*:p.R212W variant displayed elevated mutant dynorphin A, resulting in Purkinje cell loss and motor dysfunction and recapitulation of clinical features in human cases of spinocerebellar ataxia (PMID: 26169942). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebellar Ataxia Gene Curation Expert Panel on the meeting date August 12th, 2026 (SOP Version 12).

spinocerebellar ataxia type 23SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012449

Submitter: Orphanet

spinocerebellar ataxia type 23STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012449

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 23STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012449

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 23AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 15306549; 21035104

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDYN variants in ClinVar

5 Conditions Cataloged

not providedTotal: 122

Inborn genetic diseasesTotal: 45

Spinocerebellar ataxia type 23Total: 28

not specifiedTotal: 28

PDYN-related disorderTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024411.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	30 clinvar	3 clinvar	35
missense	1 clinvar	1 clinvar	96 clinvar	16 clinvar	1 clinvar	115
nonsense			3 clinvar			3
start loss			1 clinvar			1
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	1	108	46	4	160

Highest pathogenic variant AF is 0.000018585633

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024411.5	RefSeq	NP_077722.1	2	MANE Select
ENST00000217305.3	Ensembl	ENSP00000217305.2	2	MANE Select
NM_001190892.1	RefSeq	NP_001177821.1	2	Standard
NM_001190898.3	RefSeq	NP_001177827.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Amphetamine addiction - Homo sapiens (human)
Alcoholism - Homo sapiens (human)
Cocaine addiction - Homo sapiens (human)
Spinal Cord Injury
Signaling by GPCR

Biological Process

G protein-coupled receptor signaling pathway
neuropeptide signaling pathway
chemical synaptic transmission
regulation of signaling receptor activity

Molecular Function

opioid peptide activity
opioid receptor binding

Cellular Component

extracellular region
plasma membrane
dendrite
neuronal cell body
axon terminus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217305
Coding exons: 2
Length: 15330
Individuals with no LoFs: 125676
Homozygous LoFs: 1
Heterozygous LoFs: 71
Defined: 125748
p: 0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.527	159	141	1.12	0.00000904	1644
Missense (PolyPhen)		59	49.926	1.1817		495
Synonymous	-0.607	66	60.0	1.10	0.00000343	515
Loss of Function	0.295	6	6.83	0.878	2.99e-7	100

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.00082	0.00078	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Leu-enkephalins compete with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress (By similarity). {ECO:0000250}.; FUNCTION: Leumorphin has a typical opiod activity and may have anti-apoptotic effect. {ECO:0000250}.;
Disease: DISEASE: Spinocerebellar ataxia 23 (SCA23) [MIM:610245]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA23 is an adult-onset autosomal dominant form characterized by slowly progressive gait and limb ataxia, with variable additional features, including peripheral neuropathy and dysarthria. {ECO:0000269|PubMed:21035104, ECO:0000269|PubMed:21712028, ECO:0000269|PubMed:23108490, ECO:0000269|PubMed:23471613}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.187

Intolerance Scores

LoFtool: 0.213
RVIS EVS: 0.57
RVIS percentile EVS: 82.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.126

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium