PARP4

Chr 13

poly(ADP-ribose) polymerase family member 4

Also known as: ADPRTL1, ARTD4, PARP-4, PARPL, PH5P, VAULT3, VPARP, VWA5C

NCBI Gene: 143 ENSG00000102699 UniProt: Q9UKK3

This gene encodes poly(ADP-ribosyl)transferase-like 1 protein, which catalyzes mono-ADP-ribosylation of target proteins and lacks the DNA-binding domain found in classical poly(ADP-ribose) polymerases. Mutations cause autosomal recessive neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain malformations. The gene shows minimal constraint against loss-of-function variants, consistent with recessive inheritance patterns.

ResearchSummary from RefSeq, UniProt

This gene encodes poly(ADP-ribosyl)transferase-like 1 protein, which is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. Since this protein is not capable of binding DNA directly, its transferase activity may be activated by other factors such as protein-protein interaction mediated by the extensive carboxyl terminus. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.84

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?

0.84LOEUF

pLI 0.000

Z-score 2.78

OE 0.67 (0.54–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.13Z-score

OE missense 0.99 (0.93–1.04)

878 obs / 888.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.54–0.84)

0≤0.351.4

Missense OE?0.99 (0.93–1.04)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 55 / 82.2Missense obs/exp: 878 / 888.6Syn Z: -0.85

Background carrier burden — how many people carry a rare variant somewhere in PARP4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 28

2,022 rare PASS variants

Rare truncating (LoF)

1 in 270

316 rare PASS variants

Rare synonymous (reference)

1 in 54

713 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PARP4. 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 38	1 in 380
South Asian	~43k	1 in 24	1 in 180
Remaining (unassigned)	~30k	1 in 21	1 in 270
European (Finnish)	~27k	1 in 69	1 in 1,700
Admixed American	~22k	1 in 25	1 in 570
African / African American	~21k	1 in 19	1 in 260
East Asian	~20k	1 in 32	1 in 250
Ashkenazi Jewish	~13k	1 in 86	1 in 470
Middle Eastern	~2,884	1 in 24	1 in 570

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 20 of 33 coding exons well covered in gnomAD exomes; exons 4, 5, 7, 12, 14 and 8 more marginal. Genomes: 32 of 33 (exon 34 below).? see exons ↓