Is PER2 p.His121Pro (c.362A>C) pathogenic?

PER2 p.His121Pro (c.362A>C) is classified Uncertain significance in PER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: ambiguous (0.5487); Ultra-rare (popmax 0.0154%, sas).

How common is PER2 p.His121Pro (c.362A>C) in the general population?

PER2 p.His121Pro (c.362A>C) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about PER2 p.His121Pro (c.362A>C)?

AlphaMissense predicts ambiguous (score 0.5487) — an in-silico prediction, not a clinical call.

PER2 p.His121Pro

c.362A>C · VCV3305803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5487 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5487	ambiguous
REVEL	0.279	benign-leaning
SaProt	LLR -12.52	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	27.2	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 0.0154% South Asian · 14/91,088 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.000867% 14/1,614,154 alleles · ultra-rare exomes 14/1,461,796 · genomes 0/152,358 · 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.His121Pro
Coding: c.362A>C
MANE Select: NM_022817
Type: single nucleotide variant
Location: chr2:238275829 (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.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
PER2 p.Phe393= 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-his121pro (accessed [today's date]).

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