STAP1

Chr 4

signal transducing adaptor family member 1

Also known as: BRDG1, STAP-1

NCBI Gene: 26228 ENSG00000035720 UniProt: Q9ULZ2 OMIM: 604298

STAP1 encodes a docking protein that functions in B-cell receptor signaling by interacting with and upregulating the tyrosine kinase TEC through a positive feedback loop. Mutations cause autosomal dominant hypercholesterolemia characterized by elevated LDL cholesterol levels and increased risk of coronary vascular disease. The gene shows very low constraint to loss-of-function variants (pLI 0.00002, LOEUF 1.02), suggesting tolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene contains a proline-rich region, a pleckstrin homology (PH) domain, and a region in the carboxy terminal half with similarity to the Src Homology 2 (SH2) domain. This protein is a substrate of tyrosine-protein kinase Tec, and its interaction with tyrosine-protein kinase Tec is phosphorylation-dependent. This protein is thought to participate in a positive feedback loop by upregulating the activity of tyrosine-protein kinase Tec. Variants of this gene have been associated with autosomal-dominant hypercholesterolemia (ADH), which is characterized by elevated low-density lipoprotein cholesterol levels and in increased risk of coronary vascular disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.02

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.02LOEUF

pLI 0.000

Z-score 1.50

OE 0.60 (0.37–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.03Z-score

OE missense 0.99 (0.87–1.14)

155 obs / 155.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.37–1.02)

0≤0.351.4

Missense OE?0.99 (0.87–1.14)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 10 / 16.6Missense obs/exp: 155 / 155.9Syn Z: -1.16

Background carrier burden — how many people carry a rare variant somewhere in STAP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

382 rare PASS variants

Rare truncating (LoF)

1 in 2,600

66 rare PASS variants

Rare synonymous (reference)

1 in 320

144 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for STAP1. 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 180	1 in 2,500
South Asian	~43k	1 in 170	1 in 2,600
Remaining (unassigned)	~30k	1 in 150	1 in 2,700
European (Finnish)	~27k	1 in 830	none seen
Admixed American	~22k	1 in 260	≈ 1 in 5,500
African / African American	~21k	1 in 200	1 in 1,700
East Asian	~20k	1 in 490	1 in 1,100
Ashkenazi Jewish	~13k	1 in 490	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 150	≈ 1 in 2,900

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 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓