# NM_006031.6(PCNT):c.2046G>A (p.Ser682=)

https://sugi.bio/variant/pcnt-p-ser682

## Summary

**PCNT p.Ser682= (c.2046G>A)** is classified **Likely benign** in PCNT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-24). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs201569145 · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the PCNT gene that is classified as likely benign — not considered disease-causing, 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 | [PCNT](https://sugi.bio/atlas/gene/PCNT/) |
| Protein change (HGVS p.) | p.Ser682= |
| Coding change (HGVS c.) | c.2046G>A |
| MANE Select transcript | [NM_006031](https://www.ncbi.nlm.nih.gov/nuccore/NM_006031) |
| dbSNP | [rs201569145](https://www.ncbi.nlm.nih.gov/snp/rs201569145/) |
| Variant type | single nucleotide variant |
| Location | chr21:46357083-46357083 (GRCh38) |
| ClinVar | [VCV2882731](https://www.ncbi.nlm.nih.gov/clinvar/variation/2882731/) |

**All HGVS expressions:** `NC_000021.8:g.47776998G>A`, `NC_000021.9:g.46357083G>A`, `NG_008961.2:g.37962G>A`, `NM_001315529.2:c.1692G>A`, `NM_006031.6:c.2046G>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 -4.941, GERP -2.56 — fast-evolving / accelerated position
- CADD: **PHRED 0.179**. 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, Δ0.55 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 (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00196% · FAF99 0.00168% · 1/6,060 in the highest group · 35/1,613,912 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| European (non-Finnish) | 0.00271% | 36,868 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,506 |
| South Asian | 0.0011% | 91,082 |

*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}

**PCNT** population constraint: LOEUF 0.943, pLI 1.9599e-84, missense-Z -0.4558. *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):

- **microcephalic osteodysplastic primordial dwarfism type II** — Definitive (AR)

## Protein context {#protein}

Residue **682** lies in a modified residue (phosphoserine).

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

*Describes the biological roles of PCNT (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.*


### Pathways affected {#pathways}

PCNT participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [Aggrephagy](https://reactome.org/content/detail/R-HSA-9646399) | electronic |
| [Chaperone Mediated Autophagy](https://reactome.org/content/detail/R-HSA-9613829) | electronic |
| [Late endosomal microautophagy](https://reactome.org/content/detail/R-HSA-9615710) | electronic |

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

**Biological process:** microtubule cytoskeleton organization, mitotic spindle organization, cilium assembly, positive regulation of intracellular protein transport.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-24 |

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

## Similar variants {#similar}

Related PCNT variant pages (same residue, condition, or type): [PCNT p.Ser682Trp](/variant/pcnt-p-ser682trp), [PCNT c.1032+1G>A](/variant/pcnt-c-1032-plus-1g-a), [PCNT c.1680-1G>C](/variant/pcnt-c-1680-minus-1g-c), [PCNT c.3313-2A>C](/variant/pcnt-c-3313-minus-2a-c), [PCNT c.5995-2A>C](/variant/pcnt-c-5995-minus-2a-c), [PCNT c.7024+1G>A](/variant/pcnt-c-7024-plus-1g-a), [PCNT c.7024+1G>C](/variant/pcnt-c-7024-plus-1g-c), [PCNT c.7691-1G>A](/variant/pcnt-c-7691-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2882731). 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.*