# NM_012073.5(CCT5):c.1229G>C (p.Arg410Pro)

https://sugi.bio/variant/cct5-p-arg410pro

## Summary

**CCT5 p.Arg410Pro (c.1229G>C)** is classified **Uncertain significance** in CCT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CCT5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CCT5](https://sugi.bio/atlas/gene/CCT5/) |
| Protein change (HGVS p.) | p.Arg410Pro |
| Coding change (HGVS c.) | c.1229G>C |
| MANE Select transcript | [NM_012073](https://www.ncbi.nlm.nih.gov/nuccore/NM_012073) |
| Variant type | single nucleotide variant |
| Location | chr5:10262530-10262530 (GRCh38) |
| ClinVar | [VCV3997873](https://www.ncbi.nlm.nih.gov/clinvar/variation/3997873/) |

**All HGVS expressions:** `LRG_361:g.17361G>C`, `LRG_361t1:c.1229G>C`, `NC_000005.10:g.10262530G>C`, `NC_000005.9:g.10262642G>C`, `NG_012160.1:g.17361G>C`, `NM_001306153.1:c.1166G>C`, `NM_001306154.2:c.1064G>C`, `NM_001306155.2:c.950G>C`, `NM_001306156.2:c.1115G>C`, `NM_012073.5:c.1229G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9984)
- REVEL 0.906 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.365 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 6.693, GERP 2.63, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in CCT5 (of 3,213 modeled).
- CADD: **PHRED 28.3**. 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 0.69** across the covering region of the MANE Select transcript (10,256,126–10,263,192), spanning 7,066 bp. Chi-square p 1.6e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.72 acceptor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CCT5** population constraint: LOEUF 0.235, pLI 1, missense-Z 2.3498; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 **410** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 89.34, 62% of residues very-high.

**75 experimental structure(s)** (PDB): [5UYX](https://www.rcsb.org/structure/5UYX), [5UYZ](https://www.rcsb.org/structure/5UYZ), [6NR8](https://www.rcsb.org/structure/6NR8), [6NR9](https://www.rcsb.org/structure/6NR9), [6NRA](https://www.rcsb.org/structure/6NRA), [6NRB](https://www.rcsb.org/structure/6NRB) — incl. mutant structure 5UYZ.

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

*Describes the biological roles of CCT5 (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:** CCT5's established molecular role includes mRNA 3'-UTR binding.


### Pathways affected {#pathways}

CCT5 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [BBSome-mediated cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620922) | curated |
| [Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding](https://reactome.org/content/detail/R-HSA-6814122) | curated |
| [Association of TriC/CCT with target proteins during biosynthesis](https://reactome.org/content/detail/R-HSA-390471) | electronic |
| [Folding of actin by CCT/TriC](https://reactome.org/content/detail/R-HSA-390450) | electronic |
| [Formation of tubulin folding intermediates by CCT/TriC](https://reactome.org/content/detail/R-HSA-389960) | electronic |
| [Prefoldin mediated transfer of substrate  to CCT/TriC](https://reactome.org/content/detail/R-HSA-389957) | electronic |

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

**Molecular function:** mRNA 3'-UTR binding, G-protein beta-subunit binding, protein folding chaperone, mRNA 5'-UTR binding, beta-tubulin binding.

**Biological process:** protein folding, response to virus, positive regulation of telomere maintenance via telomerase, protein stabilization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-15 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CCT5 variant pages (same residue, condition, or type): [CCT5 p.Arg410Gln](/variant/cct5-p-arg410gln), [CCT5 c.531-3C>T](/variant/cct5-c-531-minus-3c-t), [CCT5 c.*1126T>A](/variant/cct5-c-star-1126t-a), [CCT5 c.*567G>A](/variant/cct5-c-star-567g-a), [CCT5 p.Ala246Val](/variant/cct5-p-ala246val), [CCT5 p.Ala41Gly](/variant/cct5-p-ala41gly), [CCT5 p.Ala424Ser](/variant/cct5-p-ala424ser), [CCT5 p.Arg142Cys](/variant/cct5-p-arg142cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3997873). 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.*