PSTPIP1

Chr 15

proline-serine-threonine phosphatase interacting protein 1

Also known as: AICZC, CD2BP1, CD2BP1L, CD2BP1S, H-PIP, PAPA, PAPAS, PSTPIP

NCBI Gene: 9051 ENSG00000140368 UniProt: O43586

This gene encodes a cytoskeletal protein that is highly expressed in hemopoietic tissues. This protein functions via its interaction with several different proteins involved in cytoskeletal organization and inflammatory processes. It binds to the cytoplasmic tail of CD2, an effector of T cell activation and adhesion, downregulating CD2-triggered adhesion. It binds PEST-type protein tyrosine phosphatases (PTP) and directs them to c-Abl kinase to mediate c-Abl dephosphorylation, thereby, regulating c-Abl activity. It also interacts with pyrin, which is found in association with the cytoskeleton in myeloid/monocytic cells and modulates immunoregulatory functions. Mutations in this gene are associated with PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. It is hypothesized that the disease-causing mutations compromise physiologic signaling necessary for the maintenance of a proper inflammatory response. [provided by RefSeq, Mar 2016]

Research

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtPyogenic sterile arthritis, pyoderma gangrenosum, and acne

UniProtAutoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia

Clinical highlights

Interpreting a novel variant

A dominant-negative effect is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.76

LOEUF

Mechanism· G2P

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?

0.76LOEUF

pLI 0.000

Z-score 2.55

OE 0.49 (0.32–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.92Z-score

OE missense 0.84 (0.75–0.94)

215 obs / 256.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.32–0.76)

0≤0.351.4

Missense OE?0.84 (0.75–0.94)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 14 / 28.8Missense obs/exp: 215 / 256.3Syn Z: -0.93

Background carrier burden — how many people carry a rare variant somewhere in PSTPIP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 45

781 rare PASS variants

Rare truncating (LoF)

1 in 620

158 rare PASS variants

Rare synonymous (reference)

1 in 78

315 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PSTPIP1. 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 69	1 in 820
South Asian	~43k	1 in 60	1 in 1,300
Remaining (unassigned)	~30k	1 in 36	1 in 410
European (Finnish)	~27k	1 in 170	1 in 1,500
Admixed American	~22k	1 in 38	1 in 700
African / African American	~21k	1 in 48	1 in 530
East Asian	~20k	1 in 46	1 in 550
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 13,000
Middle Eastern	~2,883	1 in 58	≈ 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): All 15 coding exons well covered in gnomAD exomes and genomes.? see exons ↓