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…

GOFmechanismLOEUF 1.02

Clinical Summary— STAP1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

57 VUS of 95 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.5966th %ile

GOF

0.6736th %ile

LOF

0.2872th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

95 submitted variants in ClinVar

ClinVar

Classification Summary

VUS57

Likely Benign25

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	57	0	0	57
Likely Benign	5	1	19	25
Benign	1	0	0	1
Total	63	1	19	83

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

View in ClinVar →

4 pathogenic / likely-pathogenic (of 5) ClinVar copy-number / structural variants overlap STAP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →