# NM_006431.3(CCT2):c.527A>G (p.Lys176Arg)

https://sugi.bio/variant/cct2-p-lys176arg

## Summary

**CCT2 p.Lys176Arg (c.527A>G)** is classified **Uncertain significance** in CCT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely benign (0.0888); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2498994684 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CCT2 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 | [CCT2](https://sugi.bio/atlas/gene/CCT2/) |
| Protein change (HGVS p.) | p.Lys176Arg |
| Coding change (HGVS c.) | c.527A>G |
| MANE Select transcript | [NM_006431](https://www.ncbi.nlm.nih.gov/nuccore/NM_006431) |
| dbSNP | [rs2498994684](https://www.ncbi.nlm.nih.gov/snp/rs2498994684/) |
| Variant type | single nucleotide variant |
| Location | chr12:69589565-69589565 (GRCh38) |
| ClinVar | [VCV2131029](https://www.ncbi.nlm.nih.gov/clinvar/variation/2131029/) |

**All HGVS expressions:** `NC_000012.11:g.69983345A>G`, `NC_000012.12:g.69589565A>G`, `NM_001198842.2:c.386A>G`, `NM_006431.3:c.527A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0888)
- REVEL 0.438 (indeterminate)
- SaProt LLR -9.395 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.129, GERP 2.18, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.7**. 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 0.88** across the covering region of the MANE Select transcript (69,585,522–69,593,093), spanning 7,571 bp. Chi-square p 0.023. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}

**CCT2** population constraint: LOEUF 0.445, pLI 0.99766, missense-Z 1.2725. *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 **176** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 89.85, 70% of residues very-high.

**71 experimental structure(s)** (PDB): [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), [6NRC](https://www.rcsb.org/structure/6NRC), [6NRD](https://www.rcsb.org/structure/6NRD).

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

*Describes the biological roles of CCT2 (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:** CCT2's established molecular role includes ubiquitin protein ligase binding.


### Pathways affected {#pathways}

CCT2 participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Association of TriC/CCT with target proteins during biosynthesis](https://reactome.org/content/detail/R-HSA-390471) | other |
| [BBSome-mediated cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620922) | other |
| [Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding](https://reactome.org/content/detail/R-HSA-6814122) | other |
| [Folding of actin by CCT/TriC](https://reactome.org/content/detail/R-HSA-390450) | other |
| [Formation of tubulin folding intermediates by CCT/TriC](https://reactome.org/content/detail/R-HSA-389960) | other |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | other |
| [Prefoldin mediated transfer of substrate  to CCT/TriC](https://reactome.org/content/detail/R-HSA-389957) | other |
| [RHOBTB1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013422) | other |
| [RHOBTB2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013418) | other |

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

**Molecular function:** ubiquitin protein ligase binding, protein folding chaperone.

**Biological process:** protein folding, positive regulation of telomere maintenance via telomerase, protein stabilization, chaperone-mediated protein complex assembly, scaRNA localization to Cajal body, positive regulation of telomerase RNA localization to Cajal body.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-20 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CCT2 variant pages (same residue, condition, or type): [CCT2 p.Lys176Gln](/variant/cct2-p-lys176gln), [CCT2 p.Ala128Thr](/variant/cct2-p-ala128thr), [CCT2 p.Ala133Val](/variant/cct2-p-ala133val), [CCT2 p.Ala145Val](/variant/cct2-p-ala145val), [CCT2 p.Arg156Cys](/variant/cct2-p-arg156cys), [CCT2 p.Arg255Gln](/variant/cct2-p-arg255gln), [CCT2 p.Arg255Trp](/variant/cct2-p-arg255trp), [CCT2 p.Arg281Cys](/variant/cct2-p-arg281cys).

### 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 2131029). 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.*