Is PER2 p.Pro72Leu (c.215C>T) pathogenic?

PER2 p.Pro72Leu (c.215C>T) is classified Conflicting classifications of pathogenicity in PER2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0753); Rare (popmax 0.293%, afr).

How common is PER2 p.Pro72Leu (c.215C>T) in the general population?

PER2 p.Pro72Leu (c.215C>T) is rare (popmax 0.293%, afr) (gnomAD).

What do computational predictors say about PER2 p.Pro72Leu (c.215C>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

PER2 p.Pro72Leu

c.215C>T · rs142033533 · VCV756161

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.293%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.96	GERP -1.2, phastCons 0.001
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	12.51	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 0.293% African / African-American · 220/75,040 alleles

Filtering AF 0.261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.249%

Overall 0.0169% 272/1,614,124 alleles · rare exomes 145/1,461,812 · genomes 127/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.293%	341
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.02%	5,003
South Asian	0.0165%	6,072
European (non-Finnish)	0.00102%	98,334

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.Pro72Leu
Coding: c.215C>T
MANE Select: NM_022817
dbSNP: rs142033533
Type: single nucleotide variant
Location: chr2:238277722 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.96 · 4 PDB
Residue 72: the 'disordered' region

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

Similar variants

PER2 p.Pro72Ser Uncertain significance ★ ⚠ same residue
PER2 p.Pro72= Likely benign ★ same residue
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

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-pro72leu (accessed [today's date]).

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