Is PER2 p.Arg401Cys (c.1201C>T) pathogenic?

PER2 p.Arg401Cys (c.1201C>T) is classified Benign in PER2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0811); Low-frequency (popmax 4.53%, afr).

How common is PER2 p.Arg401Cys (c.1201C>T) in the general population?

PER2 p.Arg401Cys (c.1201C>T) is low-frequency (popmax 4.53%, afr) (gnomAD).

What do computational predictors say about PER2 p.Arg401Cys (c.1201C>T)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

PER2 p.Arg401Cys

c.1201C>T · rs77146655 · VCV767874

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.53%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.7	GERP -1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	18.61	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 4.53% African / African-American · 3,399/74,976 alleles

Filtering AF 4.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.35%

Overall 0.231% 3,723/1,613,956 alleles · low-frequency exomes 1,825/1,461,788 · genomes 1,898/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.53%	22
Remaining individualsnot grpmax-eligible	0.261%	383
Admixed American	0.193%	517
Middle Eastern	0.066%	1,516
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
South Asian	0.00439%	22,769
European (non-Finnish)	0.00288%	34,704

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.Arg401Cys
Coding: c.1201C>T
MANE Select: NM_022817
dbSNP: rs77146655
Type: single nucleotide variant
Location: chr2:238262297 (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

Similar variants

PER2 p.Arg401His Uncertain significance ★★ ⚠ same residue
PER2 p.Glu184Ala Uncertain significance ★★ ⚠ same type
PER2 p.Ala655= Benign ★★ same type
PER2 p.Arg820= Likely benign ★★ same type
PER2 p.Cys1084Arg Likely benign ★★ same type
PER2 p.His476Asn Likely benign ★★ same type
PER2 p.Phe393= Benign ★★ same type
PER2 p.Pro822= 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-arg401cys (accessed [today's date]).

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