Is PER2 p.Ala128Asp (c.383C>A) pathogenic?

PER2 p.Ala128Asp (c.383C>A) is classified Uncertain significance in PER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1942); Ultra-rare (popmax 0.0597%, nfe).

How common is PER2 p.Ala128Asp (c.383C>A) in the general population?

PER2 p.Ala128Asp (c.383C>A) is ultra-rare (popmax 0.0597%, nfe) (gnomAD).

What do computational predictors say about PER2 p.Ala128Asp (c.383C>A)?

AlphaMissense predicts likely benign (score 0.1942) — an in-silico prediction, not a clinical call.

PER2 p.Ala128Asp

c.383C>A · rs77311618 · VCV2538569

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0597%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1942	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.0048 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0597% European (non-Finnish) · 705/1,179,984 alleles

Filtering AF 0.0561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0546%

Overall 0.0473% 763/1,614,070 alleles · ultra-rare exomes 719/1,461,816 · genomes 44/152,254 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0597%	1,674
Remaining individualsnot grpmax-eligible	0.0528%	1,894
Admixed American	0.0283%	3,530
African / African-American	0.0107%	9,368

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.Ala128Asp
Coding: c.383C>A
MANE Select: NM_022817
dbSNP: rs77311618
Type: single nucleotide variant
Location: chr2:238275808 (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-ala128asp (accessed [today's date]).

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