# NM_144596.4(TTC8):c.54G>A (p.Arg18=)

https://sugi.bio/variant/ttc8-p-arg18

## Summary

**TTC8 p.Arg18= (c.54G>A)** is classified **Likely benign** in TTC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-02). Very rare (popmax 0.00892%, eas); Associated with Bardet-Biedl syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs745942356 · 2 submitters · 3 linked conditions · very rare (popmax 0.00892%, eas)

## For patients & families {#patients}

This is a change in the TTC8 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Bardet-Biedl 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive, Oligogenic |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Specific population) |
| Clinical trials | 18 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TTC8 is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Bardet-Biedl syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Retinal dystrophy — Obligate (100%)
- Cone/cone-rod dystrophy — Very frequent (99-80%)
- Obesity — Very frequent (99-80%)
- Childhood-onset truncal obesity — Very frequent (99-80%)
- Neurodevelopmental delay — Very frequent (99-80%)
- Abnormality of the genitourinary system — Frequent (79-30%)
- Hypogonadism — Frequent (79-30%)
- Abnormal oral cavity morphology — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006866/index) · [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.Arg18= |
| Coding change (HGVS c.) | c.54G>A |
| MANE Select transcript | [NM_144596](https://www.ncbi.nlm.nih.gov/nuccore/NM_144596) |
| dbSNP | [rs745942356](https://www.ncbi.nlm.nih.gov/snp/rs745942356/) |
| Variant type | single nucleotide variant |
| Location | chr14:88824761-88824761 (GRCh38) |
| ClinVar | [VCV1638195](https://www.ncbi.nlm.nih.gov/clinvar/variation/1638195/) |

**All HGVS expressions:** `NC_000014.8:g.89291105G>A`, `NC_000014.9:g.88824761G>A`, `NG_008126.2:g.5609G>A`, `NM_001288781.1:c.54G>A`, `NM_001288782.1:c.-509G>A`, `NM_001288783.1:c.-604G>A`, `NM_001366535.2:c.54G>A`, `NM_001366536.2:c.54G>A`, `NM_144596.4:c.54G>A`, `NM_198309.3:c.54G>A`, `NM_198310.3:c.54G>A`, `NR_159362.2:n.111G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 2.177, GERP 0.716, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.06**. 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 (G>T, Δ0.86 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 **0.00892%** (eas) · FAF95 0.00298% · FAF99 0.0018% · 4/44,854 in the highest group · 36/1,613,140 alleles overall — very rare (popmax 0.00892%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00892% | 11,214 |
| African / African-American | 0.00534% | 18,728 |
| European (non-Finnish) | 0.00237% | 42,134 |

*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 benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-02.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-02 |

## Associated conditions {#conditions}

[Bardet-Biedl syndrome](https://sugi.bio/atlas/disease/bardet-biedl-syndrome/), [retinitis pigmentosa 51](https://sugi.bio/atlas/disease/retinitis-pigmentosa-51/), [Bardet-Biedl syndrome 8](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-8/).

**Reported phenotype names (ClinVar):** Bardet-Biedl syndrome, Bardet-Biedl syndrome 8, Retinitis pigmentosa 51.

## Similar variants {#similar}

Related TTC8 variant pages (same residue, condition, or type): [TTC8 c.114+2T>C](/variant/ttc8-c-114-plus-2t-c), [TTC8 c.265+1G>A](/variant/ttc8-c-265-plus-1g-a), [TTC8 c.799-2A>G](/variant/ttc8-c-799-minus-2a-g), [TTC8 p.Gln187Ter](/variant/ttc8-p-gln187ter), [TTC8 p.Gln247Ter](/variant/ttc8-p-gln247ter), [TTC8 p.Gln86Ter](/variant/ttc8-p-gln86ter), [TTC8 p.Thr163=](/variant/ttc8-p-thr163), [TTC8 p.Trp226Ter](/variant/ttc8-p-trp226ter).

### 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 1638195). 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.*