Is PER2 p.Phe745Ser (c.2234T>C) pathogenic?

PER2 p.Phe745Ser (c.2234T>C) is classified Uncertain significance in PER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: ambiguous (0.4794); Very rare (popmax 0.00667%, afr).

How common is PER2 p.Phe745Ser (c.2234T>C) in the general population?

PER2 p.Phe745Ser (c.2234T>C) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about PER2 p.Phe745Ser (c.2234T>C)?

AlphaMissense predicts ambiguous (score 0.4794) — an in-silico prediction, not a clinical call.

PER2 p.Phe745Ser

c.2234T>C · VCV3305806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4794	ambiguous
REVEL	0.191	benign-leaning
SaProt	LLR -5.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 0.92, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	24.0	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 0.00667% African / African-American · 5/74,912 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,614,044 alleles · very rare exomes 2/1,461,880 · genomes 3/152,164 · 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.Phe745Ser
Coding: c.2234T>C
MANE Select: NM_022817
Type: single nucleotide variant
Location: chr2:238255743 (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-phe745ser (accessed [today's date]).

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