# NM_144596.4(TTC8):c.269del (p.Pro90fs)

https://sugi.bio/variant/ttc8-p-pro90fs

## Summary

**TTC8 p.Pro90fs (c.269del)** is classified **Likely pathogenic** in TTC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-15). Very rare (popmax 8.48e-05%, nfe); Associated with TTC8-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the TTC8 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to TTC8-related 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.*

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TTC8](https://sugi.bio/atlas/gene/TTC8/) |
| Protein change (HGVS p.) | p.Pro90fs |
| Coding change (HGVS c.) | c.269del |
| MANE Select transcript | [NM_144596](https://www.ncbi.nlm.nih.gov/nuccore/NM_144596) |
| Variant type | Deletion |
| Location | chr14:88840866-88840866 (GRCh38) |
| ClinVar | [VCV4922820](https://www.ncbi.nlm.nih.gov/clinvar/variation/4922820/) |

**All HGVS expressions:** `NC_000014.8:g.89307212del`, `NC_000014.9:g.88840868del`, `NG_008126.2:g.21716del`, `NM_001288781.1:c.239del`, `NM_001288782.1:c.-324del`, `NM_001288783.1:c.-419del`, `NM_001366535.2:c.239del`, `NM_001366536.2:c.239del`, `NM_144596.4:c.269del`, `NM_198309.3:c.239del`, `NM_198310.3:c.239del`, `NR_159362.2:n.296del`

## 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 11.822, GERP 1.32, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.8, pLI 5.2419e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,936 in the highest group · 1/1,613,986 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**TTC8** population constraint: LOEUF 0.8, pLI 5.2419e-08, missense-Z 0.60385; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **TTC8-related ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.48, 57% of residues very-high.

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

*Describes the biological roles of TTC8 (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:** TTC8's established molecular role includes RNA polymerase II-specific DNA-binding transcription factor binding.


### Pathways affected {#pathways}

TTC8 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [BBSome-mediated cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620922) | curated |

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

**Molecular function:** RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** establishment of anatomical structure orientation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-08-15 |

## Associated conditions {#conditions}

[TTC8-related disorder](https://sugi.bio/atlas/disease/ttc8-related-disorder/).

**Reported phenotype names (ClinVar):** TTC8-related disorder, TTC8-related condition.

## Similar variants {#similar}

Related TTC8 variant pages (same residue, condition, or type): [TTC8 p.Lys19fs](/variant/ttc8-p-lys19fs), [TTC8 c.265+1G>A](/variant/ttc8-c-265-plus-1g-a), [TTC8 p.Gln86Ter](/variant/ttc8-p-gln86ter), [TTC8 p.Thr163=](/variant/ttc8-p-thr163), [TTC8 p.Trp226Ter](/variant/ttc8-p-trp226ter), [TTC8 p.Arg347Trp](/variant/ttc8-p-arg347trp), [TTC8 p.Asn426Ile](/variant/ttc8-p-asn426ile), [TTC8 c.144+1G>T](/variant/ttc8-c-144-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 4922820). 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.*