TIPRL

Chr 1

TOR signaling pathway regulator

Also known as: TIP, TIP41, TIPRL1

NCBI Gene: 261726 ENSG00000143155 UniProt: O75663 OMIM: 611807

TIPRL encodes an inhibitory regulator of protein phosphatases PP2A, PP4, and PP6, which are critical enzymes involved in cellular signaling and DNA damage response pathways. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants (pLI 0.95, LOEUF 0.34), indicating that complete loss of protein function is likely not tolerated in humans.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

TIPRL is an inhibitory regulator of protein phosphatase-2A (PP2A) (see PPP2CA; MIM 176915), PP4 (see PPP4C; MIM 602035), and PP6 (see PPP6C; MIM 612725) (McConnell et al., 2007 [PubMed 17384681]).[supplied by OMIM, Nov 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOEUF 0.34

Clinical Summary— TIPRL

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

21 VUS of 36 total submissions

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GeneReview available — TIPRL

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.954

Z-score 3.23

OE 0.07 (0.02–0.34)

Highly constrained

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

Missense Constraint?

1.80Z-score

OE missense 0.58 (0.48–0.69)

84 obs / 144.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.02–0.34)

0≤0.351.4

Missense OE?0.58 (0.48–0.69)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 1 / 14.1Missense obs/exp: 84 / 144.9Syn Z: 0.70

ClinVar Variant Classifications

36 submitted variants in ClinVar

ClinVar

Classification Summary

VUS21

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	21	21
Likely Benign	0	0
Benign	0	0
Total	21	21

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap TIPRL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →