POLA2

Chr 11

DNA polymerase alpha 2, accessory subunit

NCBI Gene: 23649 ENSG00000014138 UniProt: Q14181 OMIM: 620063

POLA2 encodes the accessory subunit of the DNA polymerase alpha complex, which is essential for initiating DNA synthesis during the S phase of the cell cycle by recruiting the complex to replicative forks and facilitating primer extension. The gene is highly constrained against loss-of-function variants, indicating mutations are likely to cause severe developmental consequences. Pathogenic variants in POLA2 cause autosomal recessive microcephalic primordial dwarfism with severe intellectual disability, typically manifesting in early infancy with growth restriction and neurodevelopmental delays.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable DNA binding activity. Involved in DNA replication initiation and DNA replication, synthesis of primer. Located in nucleoplasm. Part of alpha DNA polymerase:primase complex. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.65

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.000

Z-score 3.29

OE 0.43 (0.30–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.06Z-score

OE missense 0.84 (0.76–0.92)

278 obs / 332.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.30–0.65)

0≤0.351.4

Missense OE?0.84 (0.76–0.92)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 17 / 39.2Missense obs/exp: 278 / 332.3Syn Z: 0.19

Background carrier burden — how many people carry a rare variant somewhere in POLA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

729 rare PASS variants

Rare truncating (LoF)

1 in 1,500

102 rare PASS variants

Rare synonymous (reference)

1 in 120

315 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for POLA2. 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 120	1 in 1,900
South Asian	~43k	1 in 72	1 in 750
Remaining (unassigned)	~30k	1 in 91	1 in 1,400
European (Finnish)	~27k	1 in 180	1 in 3,300
Admixed American	~22k	1 in 130	1 in 1,000
African / African American	~21k	1 in 61	1 in 1,600
East Asian	~20k	1 in 120	1 in 1,200
Ashkenazi Jewish	~13k	1 in 520	none seen
Middle Eastern	~2,884	1 in 72	≈ 1 in 1,400

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): 15 of 18 coding exons well covered in gnomAD exomes; exons 3, 4, 13 marginal. Genomes: all 18.? see exons ↓