Is PER3 p.Pro266Ser (c.796C>T) pathogenic?

PER3 p.Pro266Ser (c.796C>T) is classified Uncertain significance in PER3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: ambiguous (0.3719); Very rare (popmax 0.00214%, nfe).

How common is PER3 p.Pro266Ser (c.796C>T) in the general population?

PER3 p.Pro266Ser (c.796C>T) is very rare (popmax 0.00214%, nfe) (gnomAD).

What do computational predictors say about PER3 p.Pro266Ser (c.796C>T)?

AlphaMissense predicts ambiguous (score 0.3719) — an in-silico prediction, not a clinical call.

PER3 p.Pro266Ser

c.796C>T · rs756740995 · VCV2488158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00214%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3719	ambiguous
REVEL	0.289	benign-leaning
SaProt	LLR -11.49	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 3.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 45 kb · p 0.002 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P265S vs ClinVar P266S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00214% European (non-Finnish) · 25/1,167,586 alleles

Filtering AF 0.00147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00157% 25/1,595,776 alleles · very rare exomes 25/1,444,306 · genomes 0/151,470 · 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: PER3
Protein: p.Pro266Ser
Coding: c.796C>T
MANE Select: NM_001377275
dbSNP: rs756740995
Type: single nucleotide variant
Location: chr1:7801115 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.62
Residue 265 UniProt numbering: the pas 2 domain

Full PER3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PER3 p.Arg157His Uncertain significance ★★ ⚠ same type
PER3 p.Asn572Thr Uncertain significance ★★ ⚠ same type
PER3 p.Ala980= Benign ★★ same type
PER3 p.Cys1185Ser Benign ★★ same type
PER3 p.Ile614= Benign ★★ same type
PER3 p.Leu937= Likely benign ★★ same type
PER3 p.Thr527Ala Likely benign ★★ same type
PER3 p.Thr983= Benign/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/per3-p-pro266ser (accessed [today's date]).

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