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…

LOFmechanismXLRLOEUF 0.052 OMIM phenotypes

Clinical Summary— POLA1

🧬

Gene-Disease Validity (ClinGen)

X-linked reticulate pigmentary disorder · XLModerate

Moderate evidence — consider for supplementary testing

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 466 VUS of 1111 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePOLA1-related pigmentary disorder, reticulate, with systemic manifestationsLOFXLR

definitivePOLA1-related Van Esch-O'Driscoll syndromeLOFXLR

This gene — mechanism propensity

0.2798th %ile

GOF

0.2298th %ile

LOF

0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 17% of P/LP variants are LoF · LOEUF 0.05

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

1111 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic6

VUS466

Likely Benign343

Benign70

Conflicting27

Pathogenic

Likely Pathogenic

466

VUS

343

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	3	2	0	6
Likely Pathogenic	1	5	0	0	6
VUS	5	424	34	3	466
Likely Benign	0	32	132	179	343
Benign	0	20	27	23	70
Conflicting	—				27
Total	7	484	195	205	918

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

View in ClinVar →

74 pathogenic / likely-pathogenic (of 89) ClinVar copy-number / structural variants overlap POLA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →