POLGARF

Chr 15

POLG alternative reading frame

Also known as: ORF-Y

NCBI Gene: 125316803 ENSG00000291307 UniProt: A0A3B3IS91 OMIM: 620759

POLGARF encodes a 260 amino acid protein that may interact with P32 (C1QBP), a mitochondrial matrix protein involved in mitochondrial genome-encoded protein expression, and potentially sequesters P32 in the nucleolus. Some disease-causing mutations previously attributed to POLG may actually be associated with POLGARF, though the specific phenotypes and inheritance pattern for POLGARF mutations remain to be fully characterized. This gene uses an alternate reading frame of the POLG transcript, making it a distinct protein product from POLG isoforms.

OMIM ResearchSummary from RefSeq

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. [provided by RefSeq, May 2022]

OMIM ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— POLGARF

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ClinVar Variants

61 unique Pathogenic / Likely Pathogenic· 373 VUS of 723 total submissions

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Some data sources returned errors (1)

gnomad: Error: Gene not found

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

This gene — mechanism propensity

0.3793th %ile

GOF

0.6931th %ile

LOF

0.4528th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

LOF75% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

723 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic35

VUS373

Likely Benign218

Benign19

Conflicting50

Pathogenic

Likely Pathogenic

373

VUS

218

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	22	4	0	0	26
Likely Pathogenic	24	10	0	1	35
VUS	2	359	10	2	373
Likely Benign	1	32	48	137	218
Benign	0	3	16	0	19
Conflicting	—				50
Total	49	408	74	140	721

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap POLGARF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →