Is PER2 p.Ala664= (c.1992G>A) pathogenic?

PER2 p.Ala664= (c.1992G>A) is classified Benign in PER2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-11). Common (popmax 13.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with PER2-related disorder.

What condition is associated with PER2 p.Ala664= (c.1992G>A)?

PER2 p.Ala664= (c.1992G>A) is associated with PER2-related disorder (ClinVar).

PER2 p.Ala664=

Q: How common is PER2 p.Ala664= (c.1992G>A) in the general population?

PER2 p.Ala664= (c.1992G>A) is common (popmax 13.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1992G>A · rs2304670 · VCV3055371

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 13.9%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

PER2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -2.9
Overall
CADD	10.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.9% South Asian · 12,698/91,062 alleles

Filtering AF 13.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.7%

Overall 9.2% 148,392/1,613,452 alleles · common exomes 133,524/1,461,182 · genomes 14,868/152,270 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	16.5%	6
South Asiangrpmax	13.9%	7
Middle Eastern	13.8%	7
Ashkenazi Jewishnot grpmax-eligible	12.5%	8
African / African-American	10.5%	10
Remaining individualsnot grpmax-eligible	9.67%	10
European (non-Finnish)	8.6%	12
Amishnot grpmax-eligible	8.55%	12
East Asian	5.84%	17
Admixed American	4.35%	23

Finnish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PER2
Protein: p.Ala664=
Coding: c.1992G>A
MANE Select: NM_022817
dbSNP: rs2304670
Type: single nucleotide variant
Location: chr2:238256995 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.96 · 4 PDB
Residue 664: the 'csnk1e binding domain' region

Full PER2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PER2-related disorder

Similar variants

PER2 p.Ala664Val Benign same residue
PER2 c.3275-1G>A Uncertain significance ★ same condition
PER2 c.1153+10C>G Likely benign same condition
PER2 c.1542+4C>T Likely benign same condition
PER2 c.1775+4T>C Likely benign same condition
PER2 c.448+8G>T Likely benign same condition
PER2 p.Ala695= Likely benign same condition
PER2 p.Gln545= Likely benign same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/per2-p-ala664 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown