Is PRKN p.Arg366Trp (c.1096C>T) pathogenic?

PRKN p.Arg366Trp (c.1096C>T) is classified Conflicting classifications of pathogenicity in PRKN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.2568); Rare (popmax 0.624%, eas); Associated with autosomal recessive juvenile Parkinson disease 2.

What condition is associated with PRKN p.Arg366Trp (c.1096C>T)?

PRKN p.Arg366Trp (c.1096C>T) is associated with autosomal recessive juvenile Parkinson disease 2 (ClinVar).

How common is PRKN p.Arg366Trp (c.1096C>T) in the general population?

PRKN p.Arg366Trp (c.1096C>T) is rare (popmax 0.624%, eas) (gnomAD).

How is Young-onset Parkinson disease inherited?

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

What do computational predictors say about PRKN p.Arg366Trp (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.2568) — an in-silico prediction, not a clinical call.

PRKN p.Arg366Trp

c.1096C>T · rs56092260 · VCV41220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2568 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.624%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive juvenile Parkinson disease 2

Computational evidence

Protein change
AlphaMissense	0.2568	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -10.83	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,378 kb · p 0.013 · regional, not allelic
Overall
CADD	28.8	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 0.624% East Asian · 280/44,878 alleles

Filtering AF 0.564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.54%

Overall 0.0216% 349/1,613,850 alleles · rare exomes 321/1,461,644 · genomes 28/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.624%	160
African / African-American	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.00439%	22,769
European (non-Finnish)	0.00407%	24,579

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: PRKN
Protein: p.Arg366Trp
Coding: c.1096C>T
MANE Select: NM_004562
dbSNP: rs56092260
Type: single nucleotide variant
Location: chr6:161386865 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.10 · 21 PDB
Residue 366: a turn; a UniProt-annotated variant site (in); the 'triad supradomain' region

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

Disease context

autosomal recessive juvenile Parkinson disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Young-onset Parkinson disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PRKN p.Arg366Gln Uncertain significance ★ ⚠ same residue
PRKN p.Arg275Trp Pathogenic/Likely pathogenic ★★ same condition
PRKN p.Arg33Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRKN p.Arg42Pro Pathogenic ★★ same condition
PRKN p.Cys212Tyr Pathogenic ★★ same condition
PRKN p.Cys253Tyr Pathogenic/Likely pathogenic ★★ same condition
PRKN p.Cys441Arg Pathogenic/Likely pathogenic ★★ same condition
PRKN p.Gln25Ter Pathogenic/Likely pathogenic ★★ same condition

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/prkn-p-arg366trp (accessed [today's date]).

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