# NM_001102401.4(TTI2):c.138T>C (p.Asn46=)

https://sugi.bio/variant/tti2-p-asn46

## Summary

**TTI2 p.Asn46= (c.138T>C)** is classified **Benign** in TTI2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-10). Common (popmax 66.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs3098657 · 3 submitters · 1 linked condition · common (popmax 66.8%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the TTI2 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters, and is linked to severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017611/index) · [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.Asn46= |
| Coding change (HGVS c.) | c.138T>C |
| MANE Select transcript | [NM_001102401](https://www.ncbi.nlm.nih.gov/nuccore/NM_001102401) |
| dbSNP | [rs3098657](https://www.ncbi.nlm.nih.gov/snp/rs3098657/) |
| Variant type | single nucleotide variant |
| Location | chr8:33512476-33512476 (GRCh38) |
| ClinVar | [VCV1342858](https://www.ncbi.nlm.nih.gov/clinvar/variation/1342858/) |

**All HGVS expressions:** `NC_000008.10:g.33369994A>G`, `NC_000008.11:g.33512476A>G`, `NG_033257.1:g.5710T>C`, `NM_001102401.4:c.138T>C`, `NM_001265581.2:c.138T>C`, `NM_001330505.3:c.138T>C`, `NM_025115.5:c.138T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 66.8%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -0.401, GERP -4.2 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.794**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.87 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **66.8%** (afr) · FAF95 66.3% · FAF99 66.1% · 50,041/74,950 in the highest group · 1,011,956/1,613,874 alleles overall — common (popmax 66.8%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 66.8% | 1 |
| Amish (not grpmax-eligible) | 66.6% | 2 |
| Finnish (not grpmax-eligible) | 65% | 2 |
| European (non-Finnish) | 64.4% | 2 |
| Remaining individuals (not grpmax-eligible) | 63.1% | 2 |
| Middle Eastern | 61.1% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 59.3% | 2 |
| East Asian | 56.6% | 2 |
| South Asian | 50.3% | 2 |
| Admixed American | 47.1% | 2 |

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-09-10.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2019–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-09-10 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-09-24 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[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):** Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome, TTI2-related disorder, not provided, TTI2-related condition, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided, Intellectual developmental disorder, autosomal recessive 39.

## Similar variants {#similar}

Related TTI2 variant pages (same residue, condition, or type): [TTI2 p.Asn46Ser](/variant/tti2-p-asn46ser), [TTI2 p.Arg334Gln](/variant/tti2-p-arg334gln), [TTI2 p.Arg355His](/variant/tti2-p-arg355his), [TTI2 p.Thr232Ile](/variant/tti2-p-thr232ile), [TTI2 c.-99-31C>T](/variant/tti2-c-minus-99-minus-31c-t), [TTI2 p.Glu63Gly](/variant/tti2-p-glu63gly), [TTI2 c.1115+1G>A](/variant/tti2-c-1115-plus-1g-a), [TTI2 c.1115+2T>C](/variant/tti2-c-1115-plus-2t-c).

### 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 1342858). 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.*