IQGAP1

Chr 15

IQ motif containing GTPase activating protein 1

Also known as: HUMORFA01, SAR1, p195

NCBI Gene: 8826 ENSG00000140575 UniProt: P46940 OMIM: 603379

This protein regulates actin cytoskeleton dynamics and assembly, binds to activated CDC42, associates with calmodulin, and promotes neurite outgrowth. Mutations cause neurodevelopmental disorders with intellectual disability and developmental delay. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the IQGAP family. The protein contains four IQ domains, one calponin homology domain, one Ras-GAP domain and one WW domain. It interacts with components of the cytoskeleton, with cell adhesion molecules, and with several signaling molecules to regulate cell morphology and motility. Expression of the protein is upregulated by gene amplification in two gastric cancer cell lines. [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

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P/LP missense

0.28

LOEUF· LoF intol.

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Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.998

Z-score 7.43

OE 0.19 (0.13–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.44Z-score

OE missense 0.77 (0.72–0.82)

680 obs / 884.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.13–0.28)

0≤0.351.4

Missense OE?0.77 (0.72–0.82)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 18 / 97.0Missense obs/exp: 680 / 884.6Syn Z: -1.12

Background carrier burden — how many people carry a rare variant somewhere in IQGAP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 41

1,822 rare PASS variants

Rare truncating (LoF)

1 in 1,300

170 rare PASS variants

Rare synonymous (reference)

1 in 52

823 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IQGAP1. 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 51	1 in 1,300
South Asian	~43k	1 in 48	1 in 1,100
Remaining (unassigned)	~30k	1 in 36	1 in 540
European (Finnish)	~27k	1 in 99	1 in 1,400
Admixed American	~22k	1 in 36	1 in 670
African / African American	~21k	1 in 33	1 in 1,600
East Asian	~20k	1 in 40	1 in 1,400
Ashkenazi Jewish	~13k	1 in 220	1 in 1,100
Middle Eastern	~2,884	1 in 59	≈ 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): 30 of 38 coding exons well covered in gnomAD exomes; exons 2, 4, 5, 7, 9 and 3 more marginal. Genomes: 36 of 38 (exons 20, 21 below).? see exons ↓