PIK3R1

Chr 5

phosphoinositide-3-kinase regulatory subunit 1

Also known as: AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha

NCBI Gene: 5295 ENSG00000145675 UniProt: P27986

The PIK3R1 protein is an 85 kD regulatory subunit that binds phosphatidylinositol 3-kinase to activated receptor tyrosine kinases, mediating essential insulin signaling and glucose metabolism pathways. Mutations cause autosomal recessive agammaglobulinemia and primary immunodeficiency, or autosomal dominant SHORT syndrome (short stature, hyperextensibility, ocular depression, Rieger anomaly, teething delay). This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.23), reflecting its critical role in multiple developmental and metabolic processes.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAgammaglobulinemia 7, autosomal recessive

UniProtSHORT syndrome

UniProtImmunodeficiency 36 with lymphoproliferation

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

352

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· G2P

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GeneReview available — PIK3R1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 5.61

OE 0.11 (0.06–0.23)

Highly constrained

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

Missense Constraint?

2.72Z-score

OE missense 0.62 (0.55–0.69)

245 obs / 397.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.23)

0≤0.351.4

Missense OE?0.62 (0.55–0.69)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 5 / 46.1Missense obs/exp: 245 / 397.7Syn Z: 1.56

Background carrier burden — how many people carry a rare variant somewhere in PIK3R1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

710 rare PASS variants

Rare truncating (LoF)

1 in 2,000

71 rare PASS variants

Rare synonymous (reference)

1 in 120

327 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PIK3R1. 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 140	1 in 1,700
South Asian	~43k	1 in 100	1 in 2,600
Remaining (unassigned)	~30k	1 in 130	1 in 2,100
European (Finnish)	~27k	1 in 290	≈ 1 in 8,900
Admixed American	~22k	1 in 110	1 in 1,800
African / African American	~21k	1 in 110	1 in 2,700
East Asian	~20k	1 in 120	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,100	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 140	none seen

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.