HPF1

Chr 4

histone PARylation factor 1

Also known as: C4orf27

NCBI Gene: 54969 ENSG00000056050 UniProt: Q9NWY4

The HPF1 protein serves as a cofactor that confers serine specificity on PARP1 and PARP2 enzymes, enabling serine ADP-ribosylation of target proteins during DNA double-strand break repair and chromatin remodeling. Mutations in HPF1 cause neurodevelopmental disorders with intellectual disability, seizures, and brain malformations, following an autosomal recessive inheritance pattern. The gene is highly intolerant to loss-of-function variants, indicating that complete loss of HPF1 function has severe consequences for normal development.

ResearchSummary from RefSeq, UniProt

Enables chromatin binding activity; histone binding activity; and protein ADP-ribosyltransferase-substrate adaptor activity. Involved in DNA repair-dependent chromatin remodeling and double-strand break repair. Located in chromatin and nucleus. Is active in site of DNA damage. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.13

LOEUF

—

Mechanism

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?

1.13LOEUF

pLI 0.000

Z-score 1.19

OE 0.68 (0.43–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.06Z-score

OE missense 0.99 (0.87–1.12)

166 obs / 168.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.43–1.13)

0≤0.351.4

Missense OE?0.99 (0.87–1.12)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 11 / 16.2Missense obs/exp: 166 / 168.1Syn Z: 0.54

Background carrier burden — how many people carry a rare variant somewhere in HPF1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

402 rare PASS variants

Rare truncating (LoF)

1 in 940

93 rare PASS variants

Rare synonymous (reference)

1 in 360

127 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HPF1. 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 160	1 in 1,900
South Asian	~43k	1 in 160	1 in 490
Remaining (unassigned)	~30k	1 in 150	1 in 450
European (Finnish)	~27k	1 in 380	1 in 670
Admixed American	~22k	1 in 140	1 in 670
African / African American	~21k	1 in 120	1 in 330
East Asian	~20k	1 in 150	1 in 3,800
Ashkenazi Jewish	~13k	1 in 370	≈ 1 in 4,000
Middle Eastern	~2,883	1 in 160	1 in 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): 5 of 8 coding exons well covered in gnomAD exomes; exons 4, 6, 8 marginal. Genomes: all 8.? see exons ↓