TTI1

Chr 20

TELO2 interacting protein 1

Also known as: KIAA0406, NEDMIM, smg-10

NCBI Gene: 9675 ENSG00000101407 UniProt: O43156

TTI1 encodes a regulator of the DNA damage response and stabilizes phosphatidylinositol 3-kinase-related protein kinases, while also promoting assembly and maintaining activity of mTORC1 and mTORC2 complexes that regulate cell growth and survival. Autosomal recessive mutations cause neurodevelopmental disorder with microcephaly and movement abnormalities. The gene shows low constraint to loss-of-function variation, consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

Involved in positive regulation of DNA damage checkpoint and regulation of TOR signaling. Located in cytoplasm. Part of TORC1 complex; TORC2 complex; and TTT Hsp90 cochaperone complex. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.82

Clinical Summary— TTI1

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 195 VUS of 247 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.82LOEUF

pLI 0.000

Z-score 2.42

OE 0.57 (0.40–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.22Z-score

OE missense 0.97 (0.91–1.04)

545 obs / 559.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.40–0.82)

0≤0.351.4

Missense OE?0.97 (0.91–1.04)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 21 / 36.9Missense obs/exp: 545 / 559.6Syn Z: -0.72

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateTTI1-related microcephaly, intellectual disability and ataxiaOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6356th %ile

GOF

0.5660th %ile

LOF

0.2874th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

247 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic7

VUS195

Likely Benign25

Benign4

Pathogenic

Likely Pathogenic

195

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	2	5	0	0	7
VUS	5	190	0	0	195
Likely Benign	0	7	1	17	25
Benign	0	0	1	3	4
Total	9	204	2	20	235

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap TTI1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →