Is PRKN p.Arg42Pro (c.125G>C) pathogenic?

PRKN p.Arg42Pro (c.125G>C) is classified Pathogenic in PRKN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-05). AlphaMissense: likely pathogenic (0.9261); Ultra-rare (popmax 0.0554%, mid); Associated with autosomal recessive juvenile Parkinson disease 2.

What condition is associated with PRKN p.Arg42Pro (c.125G>C)?

PRKN p.Arg42Pro (c.125G>C) is associated with autosomal recessive juvenile Parkinson disease 2 (ClinVar).

How common is PRKN p.Arg42Pro (c.125G>C) in the general population?

PRKN p.Arg42Pro (c.125G>C) is ultra-rare (popmax 0.0554%, mid) (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.Arg42Pro (c.125G>C)?

AlphaMissense predicts likely pathogenic (score 0.9261) — an in-silico prediction, not a clinical call.

PRKN p.Arg42Pro

c.125G>C · rs368134308 · VCV644125

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9261 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0554%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive juvenile Parkinson disease 2

Computational evidence

Protein change
AlphaMissense	0.9261	likely pathogenic ✓ concordant with ClinVar
REVEL	0.74	pathogenic-leaning
SaProt	LLR -13.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 0.18, phastCons 0.48
Regional constraint	o/e 1.10	unconstrained · MANE · 1,378 kb · p 0.013 · regional, not allelic
Overall
CADD	24.5	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 0.0554% Middle Eastern · 3/5,416 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00803%

Overall 0.00415% 67/1,613,226 alleles · ultra-rare exomes 65/1,461,082 · genomes 2/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0554%	1,805
European (non-Finnish)	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.00481%	20,806
Admixed American	0.00333%	30,003

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.Arg42Pro
Coding: c.125G>C
MANE Select: NM_004562
dbSNP: rs368134308
Type: single nucleotide variant
Location: chr6:162443356 (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 42: the ubiquitin-like domain; a β-strand; a UniProt-annotated variant site (in park2 and park; induces a conformational change in the psmd4-binding site of ubl resulting in impaired proteasomal binding; decreases ubiquitination and degradation; increased aggregation; impairs the ability to ubiquitinate and degrade syt11)

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.Arg42His Conflicting classifications of pathogenicity ★ ⚠ same residue
PRKN p.Arg42Cys Likely benign ★ same residue
PRKN p.Arg275Trp Pathogenic/Likely pathogenic ★★ same condition
PRKN p.Arg33Gln Pathogenic/Likely 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-arg42pro (accessed [today's date]).

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