Is PRKN p.Ile2Val (c.4A>G) pathogenic?

PRKN p.Ile2Val (c.4A>G) is classified Uncertain significance in PRKN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-16). AlphaMissense: likely benign (0.1986); Very rare (popmax 0.000858%, nfe).

How common is PRKN p.Ile2Val (c.4A>G) in the general population?

PRKN p.Ile2Val (c.4A>G) is very rare (popmax 0.000858%, nfe) (gnomAD).

What do computational predictors say about PRKN p.Ile2Val (c.4A>G)?

AlphaMissense predicts likely benign (score 0.1986) — an in-silico prediction, not a clinical call.

PRKN p.Ile2Val

c.4A>G · rs747682986 · VCV579609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000858%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1986	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.53	gain · loss 0.26 · independent
Constraint at this position
Conservation	phyloP 3.3	GERP -0.6, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,378 kb · p 0.013 · regional, not allelic
Overall
CADD	21.3	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 0.000858% European (non-Finnish) · 10/1,166,012 alleles

Filtering AF 0.000434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000316%

Overall 0.000695% 11/1,583,762 alleles · very rare exomes 9/1,431,688 · genomes 2/152,074 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00165%	60,614
European (non-Finnish)grpmax	0.000858%	116,601

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: PRKN
Protein: p.Ile2Val
Coding: c.4A>G
MANE Select: NM_004562
dbSNP: rs747682986
Type: single nucleotide variant
Location: chr6:162727665 (GRCh38)

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

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-ile2val (accessed [today's date]).

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