# NM_001102401.4(TTI2):c.695C>T (p.Thr232Ile)

https://sugi.bio/variant/tti2-p-thr232ile

## Summary

**TTI2 p.Thr232Ile (c.695C>T)** is classified **Uncertain significance** in TTI2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.28); Very rare (popmax 0.00529%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs369757546 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00529%, nfe)

## For patients & families {#patients}

This is a change in the TTI2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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.*

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TTI2](https://sugi.bio/atlas/gene/TTI2/) |
| Protein change (HGVS p.) | p.Thr232Ile |
| Coding change (HGVS c.) | c.695C>T |
| MANE Select transcript | [NM_001102401](https://www.ncbi.nlm.nih.gov/nuccore/NM_001102401) |
| dbSNP | [rs369757546](https://www.ncbi.nlm.nih.gov/snp/rs369757546/) |
| Variant type | single nucleotide variant |
| Location | chr8:33509885-33509885 (GRCh38) |
| ClinVar | [VCV437083](https://www.ncbi.nlm.nih.gov/clinvar/variation/437083/) |

**All HGVS expressions:** `NC_000008.10:g.33367403G>A`, `NC_000008.11:g.33509885G>A`, `NG_033257.1:g.8301C>T`, `NM_001102401.4:c.695C>T`, `NM_001265581.2:c.695C>T`, `NM_001330505.3:c.695C>T`, `NM_025115.2:c.695C>T`, `NM_025115.5:c.695C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.28)
- REVEL 0.246 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.49 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.761, GERP 0.739, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.6**. 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.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (33,499,176–33,512,613), spanning 13,437 bp. Chi-square p 0.23. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00529%** (nfe) · FAF95 0.00421% · FAF99 0.00382% · 62/1,172,952 in the highest group · 65/1,600,962 alleles overall — very rare (popmax 0.00529%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00529% | 18,919 |
| African / African-American | 0.00271% | 36,912 |
| Admixed American | 0.00169% | 59,210 |

*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}

**TTI2** population constraint: LOEUF 0.758, pLI 0.00014488, missense-Z 0.95273. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.85, 59% of residues very-high.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-10.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-12 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-24 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-10 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome](https://sugi.bio/atlas/disease/severe-intellectual-disability-short-stature-behavioral-abnormalities-facial-dysmorphism-syndrome/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome, Intellectual developmental disorder, autosomal recessive 39, AllHighlyPenetrant.

## Similar variants {#similar}

Related TTI2 variant pages (same residue, condition, or type): [TTI2 p.Thr232Ala](/variant/tti2-p-thr232ala), [TTI2 p.Arg334Gln](/variant/tti2-p-arg334gln), [TTI2 p.Arg355His](/variant/tti2-p-arg355his), [TTI2 p.Arg379Trp](/variant/tti2-p-arg379trp), [TTI2 p.Gly190Val](/variant/tti2-p-gly190val), [TTI2 p.Pro149Leu](/variant/tti2-p-pro149leu), [TTI2 p.Thr237Ala](/variant/tti2-p-thr237ala), [TTI2 c.-99-31C>T](/variant/tti2-c-minus-99-minus-31c-t).

### 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 437083). 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.*