SIPA1

Chr 11

signal-induced proliferation-associated 1

Also known as: SPA1

NCBI Gene: 6494 ENSG00000213445 UniProt: Q96FS4 OMIM: 602180

The protein functions as a GTPase activating protein (GAP) that specifically regulates Rap1 and Rap2 signaling by converting them to their inactive GDP-bound state and affects cell cycle progression. Mutations cause intellectual disability with seizures and language delay, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.511), indicating that such variants are likely pathogenic when they occur.

OMIM ResearchSummary from RefSeq, UniProt

The product of this gene is a mitogen induced GTPase activating protein (GAP). It exhibits a specific GAP activity for Ras-related regulatory proteins Rap1 and Rap2, but not for Ran or other small GTPases. This protein may also hamper mitogen-induced cell cycle progression when abnormally or prematurely expressed. It is localized to the perinuclear region. Two alternatively spliced variants encoding the same isoform have been characterized to date. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.51

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.005

Z-score 3.83

OE 0.31 (0.19–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.46Z-score

OE missense 0.72 (0.67–0.78)

445 obs / 616.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.31 (0.19–0.51)

0≤0.351.4

Missense OE?0.72 (0.67–0.78)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 11 / 35.7Missense obs/exp: 445 / 616.8Syn Z: 1.94

Background carrier burden — how many people carry a rare variant somewhere in SIPA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 45

1,439 rare PASS variants

Rare truncating (LoF)

1 in 1,400

177 rare PASS variants

Rare synonymous (reference)

1 in 84

736 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SIPA1. 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 57	1 in 1,700
South Asian	~43k	1 in 43	1 in 890
Remaining (unassigned)	~30k	1 in 35	1 in 680
European (Finnish)	~27k	1 in 92	1 in 910
Admixed American	~22k	1 in 35	1 in 720
African / African American	~21k	1 in 42	1 in 1,200
East Asian	~20k	1 in 53	1 in 3,500
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 2,700
Middle Eastern	~2,884	1 in 44	≈ 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): 14 of 15 coding exons well covered in gnomAD exomes; exon 9 marginal. Genomes: all 15.? see exons ↓