Is PER3 p.Pro415Ala (c.1243C>G) pathogenic?

PER3 p.Pro415Ala (c.1243C>G) is classified Conflicting classifications of pathogenicity in PER3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-16). AlphaMissense: ambiguous (0.4961); Rare (popmax 0.481%, nfe); Associated with advanced sleep phase syndrome 3.

What condition is associated with PER3 p.Pro415Ala (c.1243C>G)?

PER3 p.Pro415Ala (c.1243C>G) is associated with advanced sleep phase syndrome 3 (ClinVar).

How common is PER3 p.Pro415Ala (c.1243C>G) in the general population?

PER3 p.Pro415Ala (c.1243C>G) is rare (popmax 0.481%, nfe) (gnomAD).

How is Familial advanced sleep-phase syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PER3 p.Pro415Ala (c.1243C>G)?

AlphaMissense predicts ambiguous (score 0.4961) — an in-silico prediction, not a clinical call.

PER3 p.Pro415Ala

c.1243C>G · rs150812083 · VCV242410

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4961 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.481%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

advanced sleep phase syndrome 3

Computational evidence

Protein change
AlphaMissense	0.4961	ambiguous
REVEL	0.274	benign-leaning
SaProt	LLR -11.54	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 5.2	GERP 2.3, 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 P414A vs ClinVar P415A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.481% European (non-Finnish) · 5,669/1,179,644 alleles

Filtering AF 0.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.466%

Overall 0.493% 7,948/1,613,532 alleles · rare exomes 7,194/1,461,188 · genomes 754/152,344 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.7%	37
European (non-Finnish)grpmax	0.481%	208
Amishnot grpmax-eligible	0.439%	228
Remaining individualsnot grpmax-eligible	0.41%	244
South Asian	0.2%	500
Middle Eastern	0.149%	672
Admixed American	0.0934%	1,070
African / African-American	0.0506%	1,975
East Asian	0.00891%	11,218
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,783

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro415Ala
Coding: c.1243C>G
MANE Select: NM_001377275
dbSNP: rs150812083
Type: single nucleotide variant
Location: chr1:7809893 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.62
Residue 414 UniProt numbering: a UniProt-annotated variant site (in fasps3; decreased stability; decreased protein abundance); a UniProt-annotated variant site (in)

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

Disease context

advanced sleep phase syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial advanced sleep-phase syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

PER3 p.Asn572Thr Uncertain significance ★★ ⚠ same condition
PER3 c.3550-1G>A Uncertain significance ★ same condition
PER3 p.His417Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
PER3 p.Met57Ile Uncertain significance ★ ⚠ same condition
PER3 p.Arg50fs Uncertain significance ★ same condition
PER3 p.Arg157His Uncertain significance ★★ ⚠ same type
PER3 p.Ala980= Benign ★★ same type
PER3 p.Cys1185Ser 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-pro415ala (accessed [today's date]).

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