Is PER2 p.Ala664Val (c.1991C>T) pathogenic?

PER2 p.Ala664Val (c.1991C>T) is classified Benign in PER2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-01). AlphaMissense: likely benign (0.0559); Ultra-rare (popmax 0.099%, mid); Associated with PER2-related disorder.

What condition is associated with PER2 p.Ala664Val (c.1991C>T)?

PER2 p.Ala664Val (c.1991C>T) is associated with PER2-related disorder (ClinVar).

How common is PER2 p.Ala664Val (c.1991C>T) in the general population?

PER2 p.Ala664Val (c.1991C>T) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about PER2 p.Ala664Val (c.1991C>T)?

AlphaMissense predicts likely benign (score 0.0559) — an in-silico prediction, not a clinical call.

PER2 p.Ala664Val

c.1991C>T · rs70965448 · VCV3043837

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0559 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PER2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0559	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.33	GERP -1.7
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	6.915	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.099% Middle Eastern · 6/6,060 alleles

Filtering AF 0.0647% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0631%

Overall 0.107% 1,730/1,613,682 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.31%	76
Middle Easterngrpmax	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0768%	1,302
Ashkenazi Jewishnot grpmax-eligible	0.0743%	1,346
European (non-Finnish)	0.0686%	1,457
African / African-American	0.00533%	18,765
Admixed American	0.005%	20,010
East Asian	0.00223%	44,886
South Asian	0.0022%	45,542

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.Ala664Val
Coding: c.1991C>T
MANE Select: NM_022817
dbSNP: rs70965448
Type: single nucleotide variant
Location: chr2:238256996 (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.Ala664= 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-ala664val (accessed [today's date]).

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