POLA1

Chr XXLR

DNA polymerase alpha 1, catalytic subunit

Also known as: NSX, PDR, POLA, VEODS, p180

NCBI Gene: 5422 ENSG00000101868 UniProt: P09884 OMIM: 312040

The POLA1 gene encodes the catalytic subunit of DNA polymerase alpha, which initiates DNA synthesis during replication by extending short RNA primers before transfer to other polymerases for processive synthesis. Mutations cause X-linked recessive Van Esch-O'Driscoll syndrome and pigmentary disorder with systemic manifestations, affecting multiple organ systems including skin pigmentation. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.051), indicating that functional copies are critical for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the catalytic subunit of DNA polymerase, which together with a regulatory and two primase subunits, forms the DNA polymerase alpha complex. The catalytic subunit plays an essential role in the initiation of DNA replication. [provided by RefSeq, Mar 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Pigmentary disorder, reticulate, with systemic manifestations, X-linkedMIM #301220

XLR

Van Esch-O'Driscoll syndromeMIM #301030

XLR

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · X-linked reticulate pigmentary disorder · XL · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.05

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.05LOEUF

pLI 1.000

Z-score 7.04

OE 0.00 (0.00–0.05)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.99Z-score

OE missense 0.75 (0.69–0.82)

384 obs / 510.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.05)

0≤0.351.4

Missense OE?0.75 (0.69–0.82)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 0 / 57.7Missense obs/exp: 384 / 510.9Syn Z: -0.91

Background carrier burden — how many people carry a rare variant somewhere in POLA1?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 88

961 rare PASS variants

Rare truncating (LoF)

1 in 7,200

47 rare PASS variants

Rare synonymous (reference)

1 in 170

436 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for POLA1. 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)	~561k	1 in 110	1 in 9,600
South Asian	~36k	1 in 59	≈ 1 in 8,900
Remaining (unassigned)	~31k	1 in 84	1 in 5,800
European (Finnish)	~27k	1 in 210	≈ 1 in 7,700
Admixed American	~23k	1 in 79	≈ 1 in 6,300
African / African American	~21k	1 in 59	1 in 1,400
East Asian	~20k	1 in 78	≈ 1 in 9,600
Ashkenazi Jewish	~13k	1 in 980	1 in 2,500
Middle Eastern	~2,758	1 in 68	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): 24 of 37 coding exons well covered in gnomAD exomes; exons 6, 7, 8, 12, 13 and 8 more marginal. Genomes: all 37.? see exons ↓