POLDIP3

Chr 22

DNA polymerase delta interacting protein 3

Also known as: PDIP3, PDIP46, SKAR

NCBI Gene: 84271 ENSG00000100227 UniProt: Q9BY77 OMIM: 611520

The protein regulates translation by recruiting ribosomal protein S6 kinase beta-1 to mRNAs and enhances translational efficiency of spliced mRNAs. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early infancy. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.52), consistent with its role in fundamental cellular processes affecting neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes an RRM (RNA recognition motif)-containing protein that participates in the regulation of translation by recruiting ribosomal protein S6 kinase beta-1 to mRNAs. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.52

Clinical Summary— POLDIP3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

55 VUS of 71 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.118

Z-score 3.24

OE 0.27 (0.14–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.12Z-score

OE missense 0.98 (0.88–1.09)

247 obs / 252.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.14–0.52)

0≤0.351.4

Missense OE?0.98 (0.88–1.09)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 6 / 22.6Missense obs/exp: 247 / 252.5Syn Z: -0.66

This gene — mechanism propensity

0.6938th %ile

GOF

0.4283th %ile

LOF

0.4726th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

ClinVar Variant Classifications

71 submitted variants in ClinVar

ClinVar

Classification Summary

VUS55

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	55	55
Likely Benign	3	3
Benign	0	0
Total	58	58

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap POLDIP3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →