Is PER2 p.Arg401His (c.1202G>A) pathogenic?

PER2 p.Arg401His (c.1202G>A) is classified Uncertain significance in PER2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-23). AlphaMissense: likely benign (0.0972); Ultra-rare (popmax 0.0133%, amr); Associated with advanced sleep phase syndrome 1.

What condition is associated with PER2 p.Arg401His (c.1202G>A)?

PER2 p.Arg401His (c.1202G>A) is associated with advanced sleep phase syndrome 1 (ClinVar).

How common is PER2 p.Arg401His (c.1202G>A) in the general population?

PER2 p.Arg401His (c.1202G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is Familial advanced sleep-phase syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PER2 p.Arg401His (c.1202G>A)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

PER2 p.Arg401His

c.1202G>A · rs774249054 · VCV2434646

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

advanced sleep phase syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,978 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00161% 26/1,613,818 alleles · ultra-rare exomes 20/1,461,822 · genomes 6/151,996 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,497
Remaining individualsnot grpmax-eligible	0.0064%	15,620
East Asian	0.00446%	22,441
African / African-American	0.00401%	24,949
European (non-Finnish)	0.000763%	131,107

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.Arg401His
Coding: c.1202G>A
MANE Select: NM_022817
dbSNP: rs774249054
Type: single nucleotide variant
Location: chr2:238262296 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.96 · 4 PDB
Residue 401: the pac domain

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

Disease context

advanced sleep phase syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial advanced sleep-phase syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

PER2 p.Arg401Cys Benign ★★ same residue
PER2 c.293+1G>T Uncertain significance ★ same condition
PER2 p.Ala5Gly Uncertain significance ★ ⚠ same condition
PER2 p.Ala848Thr Uncertain significance ★ ⚠ same condition
PER2 p.Ala874Thr Uncertain significance ★ ⚠ same condition
PER2 p.Asn598Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
PER2 p.His1126Tyr Uncertain significance ★ ⚠ same condition
PER2 p.Pro988Leu Uncertain significance ★ ⚠ 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-arg401his (accessed [today's date]).

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