TPTE2

Chr 13

transmembrane phosphoinositide 3-phosphatase and tensin homolog 2

Also known as: TPIP

NCBI Gene: 93492 ENSG00000132958 UniProt: Q6XPS3

The protein acts as a lipid phosphatase that removes phosphate from the D3 position of phosphatidylinositol 3,4,5-trisphosphate, regulating cellular signaling pathways. TPTE2 mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and developmental regression. The gene shows minimal constraint against loss-of-function variants in the population.

ResearchSummary from RefSeq, UniProt

TPIP is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of inositol phospholipids.[supplied by OMIM, Jul 2002]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.94

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.82

OE 0.67 (0.49–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.05Z-score

OE missense 0.99 (0.90–1.10)

267 obs / 269.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.49–0.94)

0≤0.351.4

Missense OE?0.99 (0.90–1.10)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 24 / 35.7Missense obs/exp: 267 / 269.3Syn Z: -0.01

Background carrier burden — how many people carry a rare variant somewhere in TPTE2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

533 rare PASS variants

Rare truncating (LoF)

1 in 400

94 rare PASS variants

Rare synonymous (reference)

1 in 190

191 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TPTE2. 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 68	1 in 410
South Asian	~43k	1 in 49	1 in 200
Remaining (unassigned)	~30k	1 in 47	1 in 440
European (Finnish)	~27k	1 in 310	1 in 950
Admixed American	~22k	1 in 56	1 in 350
African / African American	~21k	1 in 67	1 in 310
East Asian	~20k	1 in 110	1 in 350
Ashkenazi Jewish	~13k	1 in 570	1 in 530
Middle Eastern	~2,881	1 in 89	1 in 320

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 18 of 20 coding exons well covered in gnomAD exomes; exons 21, 22 marginal. Genomes: 19 of 20 (exon 19 below).? see exons ↓