Is PER2 p.Arg290Cys (c.868C>T) pathogenic?

PER2 p.Arg290Cys (c.868C>T) is classified Uncertain significance in PER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-07). AlphaMissense: likely benign (0.2893); Very rare (popmax 0.0011%, sas).

How common is PER2 p.Arg290Cys (c.868C>T) in the general population?

PER2 p.Arg290Cys (c.868C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PER2 p.Arg290Cys (c.868C>T)?

AlphaMissense predicts likely benign (score 0.2893) — an in-silico prediction, not a clinical call.

PER2 p.Arg290Cys

c.868C>T · rs1373173024 · VCV2534132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2893	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -12.17	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 0.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	29.1	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 0.0011% South Asian · 1/91,086 alleles

Overall 6.2e-05% 1/1,614,090 alleles · very rare exomes 1/1,461,766 · genomes 0/152,324 · joint denominator

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.Arg290Cys
Coding: c.868C>T
MANE Select: NM_022817
dbSNP: rs1373173024
Type: single nucleotide variant
Location: chr2:238268155 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.96 · 4 PDB

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

Similar variants

PER2 p.Arg290His Uncertain significance ★ ⚠ same residue
PER2 p.Arg401His Uncertain significance ★★ ⚠ same type
PER2 p.Glu184Ala Uncertain significance ★★ ⚠ same type
PER2 p.Ala655= Benign ★★ same type
PER2 p.Arg401Cys Benign ★★ same type
PER2 p.Arg820= Likely benign ★★ same type
PER2 p.Cys1084Arg Likely benign ★★ same type
PER2 p.His476Asn Likely benign ★★ same type

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-arg290cys (accessed [today's date]).

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