# NM_022817.3(PER2):c.1635A>G (p.Gln545=)

https://sugi.bio/variant/per2-p-gln545

## Summary

**PER2 p.Gln545= (c.1635A>G)** is classified **Likely benign** in PER2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-21). Very rare (popmax 0.00133%, afr); Associated with PER2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs751149258 · 1 submitter · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the PER2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to PER2-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 | [PER2](https://sugi.bio/atlas/gene/PER2/) |
| Protein change (HGVS p.) | p.Gln545= |
| Coding change (HGVS c.) | c.1635A>G |
| MANE Select transcript | [NM_022817](https://www.ncbi.nlm.nih.gov/nuccore/NM_022817) |
| dbSNP | [rs751149258](https://www.ncbi.nlm.nih.gov/snp/rs751149258/) |
| Variant type | single nucleotide variant |
| Location | chr2:238258637-238258637 (GRCh38) |
| ClinVar | [VCV3058040](https://www.ncbi.nlm.nih.gov/clinvar/variation/3058040/) |

**All HGVS expressions:** `NC_000002.11:g.239167278T>C`, `NC_000002.12:g.238258637T>C`, `NG_012146.1:g.34930A>G`, `NM_022817.3:c.1635A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.55) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -6.062, GERP -3.24 — fast-evolving / accelerated position
- CADD: **PHRED 0.186**. 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 deltas (raw): acceptor loss **0.55**, donor loss **0.00**, acceptor gain **0.15**, donor gain **0.00**. Largest is acceptor loss, 14 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.15**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · FAF95 0.000429% · FAF99 0.000312% · 1/74,944 in the highest group · 12/1,613,926 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| African / African-American (grpmax) | 0.00133% | 74,944 |
| European (non-Finnish) | 0.000847% | 118,001 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PER2** population constraint: LOEUF 0.67, pLI 6.8266e-08, missense-Z 1.276. *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 **545** lies in the 'disordered' region; the 'csnk1e binding domain' region.

AlphaFold model confidence (whole protein): pLDDT 53.96, 16% of residues very-high.

**4 experimental structure(s)** (PDB): [6OF7](https://www.rcsb.org/structure/6OF7), [8D7M](https://www.rcsb.org/structure/8D7M), [8D7N](https://www.rcsb.org/structure/8D7N), [8D7O](https://www.rcsb.org/structure/8D7O).

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

*Describes the biological roles of PER2 (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}

PER2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of CRY and PER proteins](https://reactome.org/content/detail/R-HSA-9932298) | electronic |
| [Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes](https://reactome.org/content/detail/R-HSA-9931510) | electronic |
| [Phosphorylation and nuclear translocation of the CRY:PER:kinase complex](https://reactome.org/content/detail/R-HSA-9931530) | electronic |
| [The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex](https://reactome.org/content/detail/R-HSA-9931521) | electronic |

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-03-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-21 |

## Associated conditions {#conditions}

[PER2-related disorder](https://sugi.bio/atlas/disease/per2-related-disorder/).

**Reported phenotype names (ClinVar):** PER2-related disorder, PER2-related condition.

## Similar variants {#similar}

Related PER2 variant pages (same residue, condition, or type): [PER2 c.3275-1G>A](/variant/per2-c-3275-minus-1g-a), [PER2 c.1153+10C>G](/variant/per2-c-1153-plus-10c-g), [PER2 c.1542+4C>T](/variant/per2-c-1542-plus-4c-t), [PER2 c.1775+4T>C](/variant/per2-c-1775-plus-4t-c), [PER2 c.448+8G>T](/variant/per2-c-448-plus-8g-t), [PER2 p.Ala664=](/variant/per2-p-ala664), [PER2 p.Ala664Val](/variant/per2-p-ala664val), [PER2 p.Ala695=](/variant/per2-p-ala695).

### 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 3058040). 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.*