POLGARF

Summary

POLGARF (POLG alternative reading frame, HGNC:56246) is a protein-coding gene on chromosome 15q26.1, encoding POLG alternative reading frame (A0A3B3IS91).

This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF.

Source: NCBI Gene 125316803 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 68 total — 4 pathogenic, 2 likely-pathogenic
• MANE Select transcript: NM_001430120

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:56246
Approved symbol	POLGARF
Name	POLG alternative reading frame
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	ORF-Y
Ensembl gene	ENSG00000291307
Ensembl biotype	protein_coding
OMIM	620759
Entrez	125316803

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000706918

RefSeq mRNA: 1 — MANE Select: NM_001430120 NM_001430120

Canonical transcript exons

ENST00000706918 — 2 exons

Exon	Start	End
ENSE00003997447	89330208	89330276
ENSE00003997448	89333096	89333809

Expression profiles

Top tissues by expression

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

Regulation

Is transcription factor: no

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

POLG alternative reading frame — A0A3B3IS91 (reviewed: A0A3B3IS91)

Alternative names: ORF-Y

All UniProt accessions (1): A0A3B3IS91

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with C1QBP; the interaction results in nucleolar localization of C1QBP, probably due to prevention of C1QBP maturation and redirection from mitochondria to nucleoli.

Subcellular location. Nucleus. Nucleolus Secreted.

Post-translational modifications. Undergoes proteolytic cleavage to produce a secreted C-terminal fragment.

RefSeq proteins (1): NP_001417049* (*=MANE)

Domains & families (InterPro)

UniProt features (10 total): compositionally biased region 5, region of interest 3, chain 2

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0A3B3IS91-F1	40.89	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 2 (showing top): GOCC_NUCLEOLUS, chr15q26

GO Biological Process (0):

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

GO Cellular Component (4): obsolete extracellular space (GO:0005615), nucleolus (GO:0005730), extracellular region (GO:0005576), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1W2PPE3, A0A3B3IS91, A0A6I8MX38, A0A6I8PU40, A8MTW9, B1AH88, B3EWF7, C0HLS1, C0HMD6, H3BQW9, I3L0S3, I3L1E1, O70738, O75638, P03289, P0C880, P0DI83, P11300, P13985, P16807, P29164, P33485, P59091, P80612, Q01480, Q01900, Q3SYB3, Q5JLA7, Q5SY85, Q5T4H9, Q63003, Q6EEV4, Q6VB84, Q86SI9, Q8N1I8, Q8N1X5, Q8N319, Q8N6K4, Q8N6U2, Q8N726

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	32
Likely benign	20
Benign	2

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2822474	NM_002693.3(POLG):c.145C>T (p.Gln49Ter)	Pathogenic
3729536	NM_002693.3(POLG):c.313G>T (p.Glu105Ter)	Pathogenic
379796	NM_002693.3(POLG):c.694C>T (p.Arg232Cys)	Pathogenic
4717825	NM_002693.3(POLG):c.144_145delinsTT (p.Gln48_Gln49delinsHisTer)	Pathogenic
1677979	NM_002693.3(POLG):c.1585+2T>G	Likely pathogenic
2432810	NM_002693.3(POLG):c.18G>A (p.Trp6Ter)	Likely pathogenic

SpliceAI

235 predictions. Top by Δscore:

Variant	Effect	Δscore
15:89330274:TAC:T	acceptor_gain	1.0000
15:89330274:TACC:T	acceptor_loss	1.0000
15:89330275:ACC:A	acceptor_loss	1.0000
15:89330277:C:CA	acceptor_loss	1.0000
15:89333091:CTT:C	donor_loss	1.0000
15:89333092:TTACC:T	donor_loss	1.0000
15:89333093:TAC:T	donor_loss	1.0000
15:89333094:A:AC	donor_gain	1.0000
15:89333094:A:C	donor_loss	1.0000
15:89333094:AC:A	donor_gain	1.0000
15:89333095:C:CC	donor_gain	1.0000
15:89333095:CC:C	donor_gain	1.0000
15:89333095:CCAGG:C	donor_gain	1.0000
15:89330273:ATAC:A	acceptor_gain	0.9900
15:89330277:C:CC	acceptor_gain	0.9900
15:89330286:G:C	acceptor_gain	0.9900
15:89333095:CCA:C	donor_gain	0.9900
15:89333095:CCAG:C	donor_gain	0.9900
15:89330272:AATAC:A	acceptor_gain	0.9800
15:89330275:AC:A	acceptor_gain	0.9800
15:89330275:ACCTG:A	acceptor_gain	0.9800
15:89330276:CC:C	acceptor_gain	0.9800
15:89330286:G:GC	acceptor_gain	0.9800
15:89330273:ATACC:A	acceptor_gain	0.9700
15:89330274:TACCT:T	acceptor_gain	0.9700
15:89330276:CCTG:C	acceptor_gain	0.9700
15:89330277:C:A	acceptor_gain	0.9700
15:89330278:T:A	acceptor_gain	0.9600
15:89331072:G:C	donor_gain	0.9600
15:89333090:A:AC	donor_gain	0.9500

AlphaMissense

0 scored. Top likely-pathogenic:

Disease associations

OMIM: gene MIM:620759 | disease phenotypes: MIM:203700, MIM:303350, MIM:258450, MIM:603041, MIM:607459, MIM:613832, MIM:613662, MIM:157640

GenCC curated gene-disease

Mondo (8): mitochondrial DNA depletion syndrome 4a (MONDO:0008758), hereditary spastic paraplegia (MONDO:0019064), intellectual disability (MONDO:0001071), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (MONDO:0009783), mitochondrial DNA depletion syndrome 1 (MONDO:0011283), sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (MONDO:0011835), mitochondrial DNA depletion syndrome 4b (MONDO:0013350), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (MONDO:0024528)

Orphanet (7): Alpers-Huttenlocher syndrome (Orphanet:726), Hereditary spastic paraplegia (Orphanet:685), Autosomal recessive progressive external ophthalmoplegia (Orphanet:254886), Mitochondrial neurogastrointestinal encephalomyopathy (Orphanet:298), Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome (Orphanet:70595), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), Progressive myoclonic epilepsy type 5 (Orphanet:402082)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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)

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT03034512	Not specified	TERMINATED	Alpers Huttenlocher Natural History Study
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