# NM_001303457.2(TTI1):c.106C>T (p.Arg36Ter)

https://sugi.bio/variant/tti1-p-arg36ter

## Summary

**TTI1 p.Arg36Ter (c.106C>T)** is classified **Likely pathogenic** in TTI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-05). Very rare (popmax 0.00508%, nfe); Associated with neurodevelopmental disorder.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00508%, nfe)

## For patients & families {#patients}

This is a change in the TTI1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to neurodevelopmental disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 210 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TTI1](https://sugi.bio/atlas/gene/TTI1/) |
| Protein change (HGVS p.) | p.Arg36Ter |
| Coding change (HGVS c.) | c.106C>T |
| MANE Select transcript | [NM_001303457](https://www.ncbi.nlm.nih.gov/nuccore/NM_001303457) |
| Variant type | single nucleotide variant |
| Location | chr20:38013711-38013711 (GRCh38) |
| ClinVar | [VCV4819591](https://www.ncbi.nlm.nih.gov/clinvar/variation/4819591/) |

**All HGVS expressions:** `NC_000020.10:g.36642113G>A`, `NC_000020.11:g.38013711G>A`, `NM_001303457.2:c.106C>T`, `NM_014657.3:c.106C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.31, GERP 2.37, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.78, pLI 3.3389e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 8**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00508%** (nfe) · FAF95 0.00402% · FAF99 0.00362% · 60/1,180,032 in the highest group · 64/1,614,056 alleles overall — very rare (popmax 0.00508%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00508% | 19,667 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| Admixed American | 0.00167% | 60,006 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TTI1** population constraint: LOEUF 0.78, pLI 3.3389e-11, missense-Z 1.6011. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **36** lies in a UniProt-annotated variant site (in nedmim; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 81.38, 44% of residues very-high.

**3 experimental structure(s)** (PDB): [7F4U](https://www.rcsb.org/structure/7F4U), [7OLE](https://www.rcsb.org/structure/7OLE), [9WJY](https://www.rcsb.org/structure/9WJY).

## What this gene does {#gene-function}

*Describes the biological roles of TTI1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TTI1's established molecular role includes kinase binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** kinase binding, protein-containing complex stabilizing activity.

**Biological process:** regulation of TOR signaling, protein stabilization, positive regulation of DNA damage checkpoint.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-05.

**Submitter consensus:** unanimous (1/1 Likely Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely Pathogenic | criteria provided, single submitter | research | 2026-03-05 |

## Associated conditions {#conditions}

[neurodevelopmental disorder](https://sugi.bio/atlas/disease/neurodevelopmental-disorder/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder.

## Similar variants {#similar}

Related TTI1 variant pages (same residue, condition, or type): [TTI1 p.Val1081Met](/variant/tti1-p-val1081met), [TTI1 p.Ala806Thr](/variant/tti1-p-ala806thr), [TTI1 p.Arg519Gln](/variant/tti1-p-arg519gln), [TTI1 p.Arg724Gly](/variant/tti1-p-arg724gly), [TTI1 p.Arg869Cys](/variant/tti1-p-arg869cys), [TTI1 p.Cys86Tyr](/variant/tti1-p-cys86tyr), [TTI1 p.His229Tyr](/variant/tti1-p-his229tyr), [TTI1 p.His513Tyr](/variant/tti1-p-his513tyr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4819591). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*