POLD4

Chr 11

DNA polymerase delta 4, accessory subunit

Also known as: POLDS, p12

NCBI Gene: 57804 ENSG00000175482 UniProt: Q9HCU8

The protein is the smallest subunit of DNA polymerase delta, which performs high-fidelity DNA replication and repair including Okazaki fragment processing and broken replication fork repair. Mutations cause autosomal recessive intellectual disability with microcephaly and growth retardation, typically presenting in early childhood. The gene shows moderate tolerance to loss-of-function variants with a LOEUF score of 1.07.

ResearchSummary from RefSeq, UniProt

This gene encodes the smallest subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. The encoded protein enhances the activity of DNA polymerase delta and plays a role in fork repair and stabilization through interactions with the DNA helicase Bloom syndrome protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.07

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.145

Z-score 1.48

OE 0.34 (0.14–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.43Z-score

OE missense 0.85 (0.67–1.07)

51 obs / 60.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.14–1.07)

0≤0.351.4

Missense OE?0.85 (0.67–1.07)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 2 / 5.9Missense obs/exp: 51 / 60.3Syn Z: 0.22

Background carrier burden — how many people carry a rare variant somewhere in POLD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 300

152 rare PASS variants

Rare truncating (LoF)

1 in 1,400

48 rare PASS variants

Rare synonymous (reference)

1 in 490

70 rare PASS variants

Rare missense and truncating variants are carried at similar rates in POLD4; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 380	1 in 1,000
South Asian	~43k	1 in 170	1 in 2,000
Remaining (unassigned)	~30k	1 in 220	≈ 1 in 9,000
European (Finnish)	~27k	1 in 320	≈ 1 in 13,000
Admixed American	~22k	1 in 450	≈ 1 in 5,600
African / African American	~21k	1 in 230	1 in 1,600
East Asian	~20k	1 in 440	≈ 1 in 20,000
Ashkenazi Jewish	~13k	none seen	1 in 1,600
Middle Eastern	~2,884	1 in 330	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 4 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: 3 of 4 (exon 4 below).? see exons ↓