POLD3

Chr 11AR

DNA polymerase delta 3, accessory subunit

Also known as: IMD122, P66, P68, PPP1R128

NCBI Gene: 10714 ENSG00000077514 UniProt: Q15054 OMIM: 611415

The protein serves as an accessory component of DNA polymerase delta and zeta complexes, stabilizing these enzymes and optimizing their activity in DNA replication, repair, and translesion synthesis. Biallelic mutations cause autosomal recessive immunodeficiency 122. The gene is highly constrained against loss-of-function variants, indicating its essential role in cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the 66-kDa 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 plays a role in regulating the activity of DNA polymerase delta through interactions with other subunits and the processivity cofactor proliferating cell nuclear antigen (PCNA). Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Immunodeficiency 122MIM #620869

Clinical highlights

Gene–disease validity (ClinGen)

Limited · immunodeficiency 122 · AR · ClinGen 2025

not for standalone diagnostic reporting

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

0.24

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.998

Z-score 4.43

OE 0.07 (0.03–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.09Z-score

OE missense 0.98 (0.88–1.10)

232 obs / 235.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.24)

0≤0.351.4

Missense OE?0.98 (0.88–1.10)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 2 / 26.7Missense obs/exp: 232 / 235.7Syn Z: 0.48

Background carrier burden — how many people carry a rare variant somewhere in POLD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 88

581 rare PASS variants

Rare truncating (LoF)

1 in 1,100

69 rare PASS variants

Rare synonymous (reference)

1 in 270

191 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for POLD3. 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 140	1 in 1,400
South Asian	~43k	1 in 78	1 in 360
Remaining (unassigned)	~30k	1 in 69	1 in 1,000
European (Finnish)	~27k	1 in 400	1 in 950
Admixed American	~22k	1 in 66	1 in 440
African / African American	~21k	1 in 73	1 in 1,200
East Asian	~20k	1 in 110	1 in 1,500
Ashkenazi Jewish	~13k	1 in 720	1 in 950
Middle Eastern	~2,884	1 in 84	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): 7 of 12 coding exons well covered in gnomAD exomes; exons 2, 3, 4, 9, 10 marginal. Genomes: all 12.? see exons ↓